Cysteine-dependent inverse agonists of nuclear receptors ror-gamma/ror-gamma-t and methods of treating diseases or disorders therewith

ABSTRACT

Provided herein are compounds, compositions and methods for treating and preventing diseases and disorders, comprising administering to patients therapeutically effective amounts of cysteine-dependent inverse agonists of the nuclear receptor RORγ/RORγt. In some such embodiments, the inverse agonists bind to cysteine 476 of a nuclear receptor RORγ in the patient. Also provided are methods, as well as compounds and compositions, for modulating the activity of RORγ and RORγt by binding to the allosteric binding site through a covalent bond. In some aspects, the present disclosure relates to using compounds containing Michael acceptor groups which bind to a cysteine residue in the allosteric binding site such as cysteine 476 in RORγ.

This application claims the benefit of U.S. Provisional Application No.62/687,782, filed on Jun. 20, 2018, the entire contents of which arehereby incorporated by reference.

REFERENCE TO A SEQUENCE LISTING

The instant application contains a Sequence Listing, which has beensubmitted in ASCII format via EFS-Web and is hereby incorporated byreference in its entirety. Said ASCII copy, created on Jun. 20, 2019, isnamed REATP0106WO_ST25.txt and is 9 kilobytes in size.

BACKGROUND I. Field

The present invention relates generally to the fields of biology andmedicine. More particularly, it concerns compounds, compositions, andmethods for the treatment and prevention of diseases such as thoseassociated with RAR-related orphan receptor γ (RORγ) or RORγt and excessproduction of IL-17.

II. Description of Related Art

Since the discovery of synthetic ligands for the progesterone receptorby Djerassi and colleagues at Syntex in 1950, the field of nuclearreceptor (NR) ligand dependent transcription factors has proven fertileterritory for drug discovery and development. Not surprisingly, when thelymphocyte specific NR RORγt was shown by Littman to be both necessaryand sufficient for IL-17 expression and T helper 17 (Th17) celldifferentiation in human CD4+ T cells, a flurry of drug discoveryactivity ensued. The Th17 cell subset produces several pro-inflammatorycytokines (e.g., IL-17A, IL-17F, GM-CSF and IL-22), and has been shownto be the major pathogenic population in animal models of autoimmuneinflammation, such as the experimental autoimmune encephalomyelitis(EAE) model for multiple sclerosis and the collagen-induce arthritis(CIA) model for rheumatoid arthritis. With the FDA approval of severalbiological agents targeting the IL-17/IL-23 pathway clinical proof ofconcept for the roles of these cytokines in human autoimmune diseaseshas been unambiguously established. Vitae Pharmaceuticals was first toenter the clinic with an orally active RORγt inverse agonist, VTP43742,that showed significant efficacy in a Phase 2a psoriasis clinical study.VTP43742 and the majority of orally active agents that modulate RORγttarget the classical orthosteric binding pocket in the ligand bindingdomain (LBD) of RORγt. Recently, Merck Research Laboratories andEindhoven University have described a series of molecules thatantagonize RORγt function through binding to an allosteric site on theLBD through non-covalent interactions. Therefore, methods of modulatingthe activity of RORγ, especially RORγt, by covalent modulation of theallosteric site in the ligand binding region are of particular interest.

SUMMARY

The present disclosure provides compounds, methods and compositions thatmay be used, for example, to modulating the activity of RORγ and RORγtby binding to a cysteine residue at an allosteric site.

In one aspect, there are provided methods for treating diseases anddisorders in patients in need thereof, comprising administering to thepatient a therapeutically effective amount of a cysteine-dependentinverse agonist of the nuclear receptor RORγ/RORγt.

In another aspect, the present disclosure provides pharmaceuticalcompositions comprising a cysteine-dependent inverse agonist of nuclearreceptor RORγ/RORγt in an amount sufficient to modulate the activity ofnuclear receptor RORγ/RORγt when administered to a patient.

Either or both of the above methods and pharmaceutical compositions maybe combined with any of the following embodiments. In some embodiments,the therapeutically effective amount is sufficient to modulate theactivity of the patient's nuclear receptor RORγ/RORγt. In someembodiments, the inverse agonist binds to cysteine 476 of a nuclearreceptor RORγ in the patient. In some embodiments, the binding occursvia the formation of a covalent bond between the inverse agonist and thecysteine 476. In some embodiments, the inverse agonist binds selectivelyto cysteine 476 of a nuclear receptor RORγ in the patient. In someembodiments, the inverse agonist binds preferentially to cysteine 476 ofa nuclear receptor RORγ relative to the orthosteric binding pocket(i.e., the cholesterol binding site) in the ligand binding domain (LBD)of RORγ in the patient. In some embodiments, the inverse agonist doesnot bind to any significant extent to the orthosteric binding pocket inthe ligand binding domain (LBD) of RORγ in the patient. In someembodiments, the inverse agonist inhibits the patient's RORγ/RORγtactivity without significantly affecting the patient's RORα or RORβactivity.

In some embodiments, the method or pharmaceutical composition results inmodulating the function of the patient's RORγ/RORγt. In someembodiments, the method or pharmaceutical composition results insuppressing the patient's interleukin-17A production. In someembodiments, the method or pharmaceutical composition results inselectively inhibiting the patient's T helper 17 (Th17) celldifferentiation. In some embodiments, the inverse agonist'sRORγt-LBD-GAL4 reporter assay IC₅₀ activity is less than 1 μM. Infurther embodiments, the inverse agonist's RORγt-LBD-GAL4 reporter assayIC₅₀ activity is less than 500 nM. In still further embodiments, theinverse agonist's RORγt-LBD-GAL4 reporter assay IC₅₀ activity is lessthan 100 nM. In some embodiments, the inverse agonist's RORγt-LBD-GAL4reporter assay IC₅₀ activity is less than 1,000 nM, 950 nM, 900 nM, 850nM, 800 nM, 750 nM, 700 nM, 650 nM, 600 nM, 550 nM, 500 nM, 450 nM, 400nM, 350 nM, 300 nM, 250 nM, 200 nM, 150 nM, 100 nM, 75 nM, 50 nM, 25 nM,20 nM, 15 nM or 10 nM. In some embodiments, the inverse agonist'ssuppression of IL-17A secretion from human CD4+ T-cells assay IC₅₀activity is less than 500 nM. In further embodiments, the inverseagonist's suppression of IL-17A secretion from human CD4+ T-cells assayIC₅₀ activity is less than 100 nM. In still further embodiments, theinverse agonist's suppression of IL-17A secretion from human CD4+T-cells assay IC₅₀ activity is less than 50 nM. In some embodiments, theinverse agonist's suppression of IL-17A secretion from human CD4+T-cells assay IC₅₀ activity is less than 500 nM, 450 nM, 400 nM, 350 nM,300 nM, 250 nM, 200 nM, 150 nM, 100 nM, 75 nM, 50 nM, 25 nM, 20 nM, 15nM or 10 nM. In some embodiments, the disease or disorder is anautoimmune disease. In further embodiments, the autoimmune disease isCrohn's disease, rheumatoid arthritis, lupus, or psoriasis. In stillfurther embodiments, the autoimmune disease is rheumatoid arthritis orpsoriasis.

In some embodiments, the chemical formula of the inverse agonistcomprises a chemical group of the formula:

wherein:

-   -   the bond between carbon atoms 1 and 2 is an epoxidized double        bond or a double bond;    -   the bond between carbon atoms 4 and 5 is a single bond or a        double bond;    -   R₁ is cyano, heteroaryl_((C≤8)), substituted heteroaryl_((C≤8)),        —CF₃, or —C(O)R_(a); wherein:        -   R_(a) is hydroxy, amino, or alkoxy_((C≤8)),            alkylamino_((C≤8)), dialkylamino_((C≤8)),            alkylsulfonylamino_((C≤8)), or a substituted version of any            of these groups;    -   R₂ is hydrogen or alkyl_((C≤12)), cycloalkyl_((C≤12)),        alkenyl_((C≤12)), alkynyl_((C≤12)), aryl_((C≤12)),        aralkyl_((C≤12)), heteroaryl_((C≤12)), heteroaralkyl_((C≤12)),        acyl_((C≤12)), or a substituted version of any of these groups,        or -alkanediyl_((C≤8))-cycloalkyl_((C≤12)) or a substituted        version of this group;    -   R_(2′) is absent, hydrogen, or alkyl_((C≤12)),        cycloalkyl_((C≤12)), alkenyl_((C≤12)), alkynyl_((C≤12)),        aryl_((C≤12)), aralkyl_((C≤12)), heteroaryl_((C≤12)),        heteroaralkyl_((C≤12)), acyl_((C≤12)), or a substituted version        of these groups; provided that when the bond between carbon        atoms 4 and 5 is a double bond then R_(2′) is absent; and    -   R₃ is alkyl_((C≤12)), alkenyl_((C≤12)), aryl_((C≤12)),        aralkyl_((C≤12)), or a substituted version of any of these        groups.

In some embodiments, the formula is further defined as:

wherein:

-   -   R₁ is cyano, heteroaryl_((C≤8)), substituted heteroaryl_((C≤8)),        —CF₃, or —C(O)R_(a); wherein:        -   R_(a) is hydroxy, amino, or alkoxy_((C≤8)),            alkylamino_((C≤8)), dialkylamino_((C≤8)),            alkylsulfonylamino_((C≤8)), or a substituted version of any            of these groups;    -   R₂ is hydrogen or alkyl_((C≤12)), cycloalkyl_((C≤12)),        alkenyl_((C≤12)), alkynyl_((C≤12)), aryl_((C≤12)),        aralkyl_((C≤12)), heteroaryl_((C≤12)), heteroaralkyl_((C≤12)),        acyl_((C≤12)), or a substituted version of any of these groups,        or -alkanediyl_((C≤8))-cycloalkyl_((C≤12)) or a substituted        version of this group;    -   R_(2′) is absent, hydrogen, or alkyl_((C≤12)),        cycloalkyl_((C≤12)), alkenyl_((C≤12)), alkynyl_((C≤12)),        aryl_((C≤12)), aralkyl_((C≤12)), heteroaryl_((C≤12)),        heteroaralkyl_((C≤12)), acyl_((C≤12)), or a substituted version        of these groups; provided that when the bond between carbon        atoms 4 and 5 is a double bond then R_(2′) is absent; and    -   R₃ is alkyl_((C≤12)), alkenyl_((C≤12)), aryl_((C≤12)),        aralkyl_((C≤12)), or a substituted version of any of these        groups.

In some embodiments, the formula is further defined as:

wherein:

-   -   R₂ is hydrogen or alkyl_((C≤12)), cycloalkyl_((C≤12)),        alkenyl_((C≤12)), alkynyl_((C≤12)), aryl_((C≤12)),        aralkyl_((C≤12)), heteroaryl_((C≤12)), heteroaralkyl_((C≤12)),        acyl_((C≤12)), or a substituted version of any of these groups,        or -alkanediyl_((C≤8))-cycloalkyl_((C≤12)) or a substituted        version of this group;    -   R_(2′) is absent, hydrogen, or alkyl_((C≤12)),        cycloalkyl_((C≤12)), alkenyl_((C≤12)), alkynyl_((C≤12)),        aryl_((C≤12)), aralkyl_((C≤12)), heteroaryl_((C≤12)),        heteroaralkyl_((C≤12)), acyl_((C≤12)), or a substituted version        of these groups; provided that when the bond between carbon        atoms 4 and 5 is a double bond then R_(2′) is absent; and    -   R₃ is alkyl_((C≤12)), alkenyl_((C≤12)), aryl_((C≤12)),        aralkyl_((C≤12)), or a substituted version of any of these        groups.

In some embodiments, the formula is further defined as:

wherein:

-   -   R₂ is hydrogen or alkyl_((C≤12)), cycloalkyl_((C≤12)),        alkenyl_((C≤12)), alkynyl_((C≤12)), aryl_((C≤12)),        aralkyl_((C≤12)), heteroaryl_((C≤12)), heteroaralkyl_((C≤12)),        acyl_((C≤12)), or a substituted version of any of these groups,        or -alkanediyl_((C≤8))-cycloalkyl_((C≤12)) or a substituted        version of this group.

In some embodiments, the formula is further defined as:

In some embodiments, the inverse agonist is a compound of the formula:

wherein:

-   -   the bond between carbon atoms 1 and 2 is an epoxidized double        bond or a double bond;    -   the bond between carbon atoms 4 and 5 is a single bond or a        double bond;    -   a is 0, 1, or 2;    -   R₁ is cyano, heteroaryl_((C≤8)), substituted heteroaryl_((C≤8)),        —CF₃, or —C(O)R_(a); wherein:        -   R_(a) is hydroxy, amino, or alkoxy_((C≤8)),            alkylamino_((C≤8)), dialkylamino_((C≤8)),            alkylsulfonylamino_((C≤8)), or a substituted version of any            of these groups;    -   R₂ is hydrogen or alkyl_((C≤12)), cycloalkyl_((C≤12)),        alkenyl_((C≤12)), alkynyl_((C≤12)), aryl_((C≤12)),        aralkyl_((C≤12)), heteroaryl_((C≤12)), heteroaralkyl_((C≤12)),        acyl_((C≤12)), or a substituted version of any of these groups,        or -alkanediyl_((C≤8))-cycloalkyl_((C≤12)) or a substituted        version of this group;    -   R_(2′) is absent, hydrogen, or alkyl_((C≤12)),        cycloalkyl_((C≤12)), alkenyl_((C≤12)), alkynyl_((C≤12)),        aryl_((C≤12)), aralkyl_((C≤12)), heteroaryl_((C≤12)),        heteroaralkyl_((C≤12)), acyl_((C≤12)), or a substituted version        of these groups; provided that when the bond between carbon        atoms 4 and 5 is a double bond then R_(2′) is absent;    -   R₃ is alkyl_((C≤12)), alkenyl_((C≤12)), aryl_((C≤12)),        aralkyl_((C≤12)), or a substituted version of any of these        groups;    -   R₄ is hydrogen, amino, alkyl_((C≤18)), substituted        alkyl_((C≤18)), cycloalkyl_((C≤18)), substituted        cycloalkyl_((C≤18)), aryl_((C≤18)), substituted aryl_((C≤18)),        aralkyl_((C≤18)), substituted aralkyl_((C≤18)),        heteroaryl_((C≤18)), substituted heteroaryl_((C≤18)),        heteroaralkyl_((C≤18)), substituted heteroaralkyl_((C≤18)),        heterocycloalkyl_((C≤18)), substituted        heterocycloalkyl_((C≤18)), amido_((C≤18)), substituted        amido_((C≤18)), or

—X₁—(CH₂)_(m)—R_(4′);

-   -   wherein:        -   X₁ is NR_(b), O, or S; wherein:            -   R_(b) is hydrogen, alkyl_((C≤6)), or substituted                alkyl_((C≤6));        -   m is 0, 1, 2, 3, or 4; and        -   R_(4′) is alkyl_((C≤12)), cycloalkyl_((C≤12)),            aryl_((C≤18)), aralkyl_((C≤18)), heteroaryl_((C≤18)),            heteroaralkyl_((C≤18)), heterocycloalkyl_((C≤18)), or a            substituted version of any of these groups; or

-   -   wherein:        -   n is 0, 1, 2, 3, or 4; and        -   R_(4″) is —H, —OH, —F, —Cl, —Br, —I, —NH₂, —NO₂, —CN, —SH,            —S(O)₂OH, or —S(O)₂NH₂, or alkyl_((C≤8)),            cycloalkyl_((C≤8)), aryl_((C≤8)), heteroaryl_((C≤8)),            heterocycloalkyl_((C≤8)), acyl_((C≤8)), amido_((C≤8)),            alkoxy_((C≤8)), acyloxy_((C≤8)), alkylamino_((C≤8)),            dialkylamino_((C≤8)), —C(O)-alkoxy_((C≤8)),            —C(O)-alkylamino_((C≤8)), —C(O)-dialkyl-amino_((C≤8)),            alkylsulfonyl_((C≤8)), arylsulfonyl_((C≤8)),            alkoxysulfonyl_((C≤8)), or a substituted version of any of            these groups; or

—X₂—(CH₂)_(p)—R_(4′″);

-   -   wherein:        -   X₂ is arenediyl_((C≤12)), substituted arenediyl_((C≤12)),            heterocycloalkanediyl_((C≤12)), substituted            heterocycloalkanediyl_((C≤12)), heteroarenediyl_((C≤12)), or            substituted heteroarenediyl_((C≤12));        -   p is 0, 1, 2, 3, or 4; and        -   R_(4′″) is alkyl_((C≤8)), cycloalkyl_((C≤8)), aryl_((C≤8)),            heteroaryl_((C≤8)), heterocycloalkyl_((C≤8)), acyl_((C≤8)),            amido_((C≤8)), alkoxy_((C≤8)), acyloxy_((C≤8)),            —C(O)-alkoxy_((C≤8)), —C(O)alkylamino_((C≤8)),            —C(O)dialkyl-amino_((C≤8)), alkylsulfonyl_((C≤8)),            arylsulfonyl_((C≤8)), alkoxysulfonyl_((C≤8)), or a            substituted version of any of these groups; and    -   R₅ is amino, hydroxy, —OS(O)₂C₆H₄CH₃, alkyl_((C≤12)),        alkoxy_((C≤12)), cycloalkyl_((C≤12)), cycloalkoxy_((C≤12)),        aryl_((C≤12)), aralkyl_((C≤12)), heteroaryl_((C≤12)),        heteroaralkyl_((C≤12)), heterocycloalkyl_((C≤12)),        acyl_((C≤12)), acyloxy_((C≤12)), alkylamino_((C≤12)),        dialkylamino_((C≤12)), alkylsulfonylamino_((C≤12)), or a        substituted version of any of the last fourteen groups, or

—OY₁-A₁;

-   -   wherein:        -   Y₁ is alkanediyl_((C≤8)) or substituted alkanediyl_((C≤8));            and        -   A₁ is cycloalkyl_((C≤8)) or substituted cycloalkyl_((C≤8));            or

—Y₂—C(O)NR_(c)-A₂;

-   -   wherein:        -   Y₂ is arenediyl_((C≤8)) or substituted arenediyl_((C≤8));        -   R_(c) is hydrogen, alkyl_((C≤6)), or substituted            alkyl_((C≤6)); and        -   A₂ is aralkyl_((C≤12)) or substituted aralkyl_((C≤12)); or

-A₃R_(d);

-   -   wherein:        -   A₃ is —O— or —NR_(e)—, wherein        -   R_(e) is hydrogen, alkyl_((C≤6)), or substituted            alkyl_((C≤6)); and    -   R_(d) is acyl_((C≤12)), or substituted acyl_((C≤12));    -   provided that when carbon atoms 4 and 5 are joined by a double        bond, then R_(2′) and the hydrogen atom at carbon atom 5 are        absent;        or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is further defined as:

wherein:

-   -   the bond between carbon atoms 1 and 2 is an epoxidized double        bond or a double bond;    -   the bond between carbon atoms 4 and 5 is a single bond or a        double bond;    -   a is 0, 1, or 2;    -   R₁ is cyano, heteroaryl_((C≤8)), substituted heteroaryl_((C≤8)),        —CF₃, or —C(O)R_(a); wherein:        -   R_(a) is hydroxy, amino, or alkoxy_((C≤8)),            alkylamino_((C≤8)), dialkylamino_((C≤8)),            alkylsulfonylamino_((C≤8)), or a substituted version of any            of these groups;    -   R₂ is hydrogen or alkyl_((C≤12)), cycloalkyl_((C≤12)),        alkenyl_((C≤12)), alkynyl_((C≤12)), aryl_((C≤12)),        aralkyl_((C≤12)), heteroaryl_((C≤12)), heteroaralkyl_((C≤12)),        acyl_((C≤12)), or a substituted version of any of these groups,        or -alkanediyl_((C≤8))-cycloalkyl_((C≤12)) or a substituted        version of this group;    -   R_(2′) is absent, hydrogen, or alkyl_((C≤12)),        cycloalkyl_((C≤12)), alkenyl_((C≤12)), alkynyl_((C≤12)),        aryl_((C≤12)), aralkyl_((C≤12)), heteroaryl_((C≤12)),        heteroaralkyl_((C≤12)), acyl_((C≤12)), or a substituted version        of these groups; provided that when the bond between carbon        atoms 4 and 5 is a double bond then R_(2′) is absent;    -   R₃ is alkyl_((C≤12)), alkenyl_((C≤12)), aryl_((C≤12)),        aralkyl_((C≤12)), or a substituted version of any of these        groups;    -   R₄ is hydrogen, amino, alkyl_((C2-18)), substituted        alkyl_((C≤18)), cycloalkyl_((C≤18)), substituted        cycloalkyl_((C≤18)), aryl_((C≤18)), substituted aryl_((C≤18)),        aralkyl_((C≤18)), substituted aralkyl_((C≤18)),        heteroaryl_((C≤18)), substituted heteroaryl_((C≤18)),        heteroaralkyl_((C≤18)), substituted heteroaralkyl_((C≤18)),        heterocycloalkyl_((C≤18)), substituted        heterocycloalkyl_((C≤18)), amido_((C≤18)), substituted        amido_((C≤18)), or

—X₁—(CH₂)_(m)—R_(4′);

-   -   wherein:        -   X₁ is NR_(b), O, or S; wherein:            -   R_(b) is hydrogen, alkyl_((C≤6)), or substituted                alkyl_((C≤6));        -   m is 0, 1, 2, 3, or 4; and        -   R_(4′) is alkyl_((C≤12)), cycloalkyl_((C≤18)),            aryl_((C≤18)), aralkyl_((C≤18)), heteroaryl_((C≤18)),            heteroaralkyl_((C≤18)), heterocycloalkyl_((C≤18)), or a            substituted version of any of these groups, provided that            when X₁ is O, then R_(4′) is not methyl; or

-   -   wherein:        -   n is 0, 1, 2, 3, or 4; and        -   R_(4″) is —H, —OH, —F, —Cl, —Br, —I, —NH₂, —NO₂, —CN, —SH,            —S(O)₂OH, or —S(O)₂NH₂, or alkyl_((C≤8)),            cycloalkyl_((C≤8)), aryl_((C≤8)), heteroaryl_((C≤8)),            heterocycloalkyl_((C≤8)), acyl_((C≤8)), amido_((C≤8)),            alkoxy_((C≤8)), acyloxy_((C≤8)), alkylamino_((C≤8)),            dialkylamino_((C≤8)), —C(O)-alkoxy_((C≤8)),            —C(O)-alkylamino_((C≤8)), —C(O)-dialkyl-amino_((C≤8)),            alkylsulfonyl_((C≤8)), arylsulfonyl_((C≤8)),            alkoxysulfonyl_((C≤8)), or a substituted version of any of            these groups; or

—X₂—(CH₂)_(p)—R_(4′″);

-   -   wherein:        -   X₂ is arenediyl_((C≤12)), substituted arenediyl_((C≤12)),            heterocycloalkanediyl_((C≤12)), substituted            heterocycloalkanediyl_((C≤12)), heteroarenediyl_((C≤12)), or            substituted heteroarenediyl_((C≤12));        -   p is 0, 1, 2, 3, or 4; and        -   R_(4′″) is alkyl_((C≤8)), cycloalkyl_((C≤8)), aryl_((C≤8)),            heteroaryl_((C≤8)), heterocycloalkyl_((C≤8)), acyl_((C≤8)),            amido_((C≤8)), alkoxy_((C≤8)), acyloxy_((C≤8)),            —C(O)-alkoxy_((C≤8)), —C(O)-alkylamino_((C≤8)),            —C(O)-dialkyl-amino_((C≤8)), alkylsulfonyl_((C≤8)),            arylsulfonyl_((C≤8)), alkoxysulfonyl_((C≤8)), or a            substituted version of any of these groups; and    -   R₅ is amino, hydroxy, —OS(O)₂C₆H₄CH₃, alkyl_((C≤12)),        alkoxy_((C≤12)), cycloalkyl_((C≤12)), cycloalkoxy_((C≤12)),        aryl_((C≤12)), aralkyl_((C≤12)), heteroaryl_((C≤12)),        heteroaralkyl_((C≤12)), heterocycloalkyl_((C≤12)),        acyl_((C≤12)), acyloxy_((C≤12)), alkylamino_((C≤12)),        dialkylamino_((C≤12)), alkylsulfonylamino_((C≤12)), or a        substituted version of any of the last fourteen groups, or

—OY₁-A₁;

-   -   wherein:        -   Y₁ is alkanediyl_((C≤8)) or substituted alkanediyl_((C≤8));            and        -   A₁ is cycloalkyl_((C≤8)) or substituted cycloalkyl_((C≤8));            or

—Y₂—C(O)NR_(c)-A₂;

-   -   wherein:        -   Y₂ is arenediyl_((C≤8)) or substituted arenediyl_((C≤8));        -   R_(c) is hydrogen, alkyl_((C≤6)), or substituted            alkyl_((C≤6)); and        -   A₂ is aralkyl_((C≤12)) or substituted aralkyl_((C≤12)); or

-A₃R_(d);

-   -   wherein:        -   A₃ is —O— or —NR_(e)—, wherein            -   R_(e) is hydrogen, alkyl_((C≤6)), or substituted                alkyl_((C≤6)); and        -   R_(d) is acyl_((C≤12)), or substituted acyl_((C≤12));    -   provided that when carbon atoms 4 and 5 are joined by a double        bond, then R_(2′) and the hydrogen atom at carbon atom 5 are        absent;        or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is further defined as:

wherein:

-   -   the bond between carbon atoms 1 and 2 is an epoxidized double        bond or a double bond;    -   the bond between carbon atoms 4 and 5 is a single bond or a        double bond;    -   R₁ is cyano, heteroaryl_((C≤8)), substituted heteroaryl_((C≤8)),        —CF₃, or —C(O)R_(a); wherein:        -   R_(a) is hydroxy, amino, or alkoxy_((C≤8)),            alkylamino_((C≤8)), dialkylamino_((C≤8)),            alkylsulfonylamino_((C≤8)), or a substituted version of any            of these groups;    -   R₂ is hydrogen or alkyl_((C≤12)), cycloalkyl_((C≤12)),        alkenyl_((C≤12)), alkynyl_((C≤12)), aryl_((C≤12)),        aralkyl_((C≤12)), heteroaryl_((C≤12)), heteroaralkyl_((C≤12)),        acyl_((C≤12)), or a substituted version of any of these groups,        or -alkanediyl_((C≤8))-cycloalkyl_((C≤12)) or a substituted        version of this group;    -   R_(2′) is absent, hydrogen, alkyl_((C≤12)), cycloalkyl_((C≤12)),        alkenyl_((C≤12)), alkynyl_((C≤12)), or a substituted version of        the last four groups; provided that when the bond between carbon        atoms 4 and 5 is a double bond then R_(2′) is absent;    -   R₃ is alkyl_((C≤12)), alkenyl_((C≤12)), aryl_((C≤12)),        aralkyl_((C≤12)), or a substituted version of any of these        groups;    -   R₄ is hydrogen, amino, alkyl_((C2-18)), substituted        alkyl_((C≤18)), cycloalkyl_((C≤18)), substituted        cycloalkyl_((C≤18)), aryl_((C≤18)), substituted aryl_((C≤18)),        aralkyl_((C≤18)), substituted aralkyl_((C≤18)),        heteroaryl_((C≤18)), substituted heteroaryl_((C≤18)),        heteroaralkyl_((C≤18)), substituted heteroaralkyl_((C≤18)),        heterocycloalkyl_((C≤18)), substituted        heterocycloalkyl_((C≤18)), alkylamino_((C≤18)), substituted        alkylamino_((C≤18)), dialkylamino_((C≤18)), substituted        dialkylamino_((C≤18)), alkylthio_((C≤18)), substituted        alkylthio_((C≤18)), amido_((C≤18)), substituted amido_((C≤18)),        or

—X₁—(CH₂)_(m)—R_(4′);

-   -   wherein:        -   X₁ is NR_(b), O, or S; wherein:            -   R_(b) is hydrogen, alkyl_((C≤6)), or substituted                alkyl_((C≤6));        -   m is 0, 1, 2, 3, or 4; and        -   R_(4′) is alkyl_((C≤12)), cycloalkyl_((C≤18)),            aryl_((C≤18)), aralkyl_((C≤18)), heteroaryl_((C≤18)),            heteroaralkyl_((C≤18)), heterocycloalkyl_((C≤18)), or a            substituted version of any of these groups, provided that            when X₁ is O, then R_(4′) is not methyl; or

-   -   wherein:        -   n is 0, 1, 2, 3, or 4; and        -   R_(4″) is —H, —OH, —F, —Cl, —Br, —I, —NH₂, —NO₂, —CN, —SH,            —S(O)₂OH, or —S(O)₂NH₂, or alkyl_((C≤8)),            cycloalkyl_((C≤8)), aryl_((C≤8)), heteroaryl_((C≤8)),            heterocycloalkyl_((C≤8)), acyl_((C≤8)), amido_((C≤8)),            alkoxy_((C≤8)), acyloxy_((C≤8)), alkylamino_((C≤8)),            dialkylamino_((C≤8)), —C(O)-alkoxy_((C≤8)),            —C(O)-alkylamino_((C≤8)), —C(O)-dialkyl-amino_((C≤8)),            alkylsulfonyl_((C≤8)), arylsulfonyl_((C≤8)),            alkoxysulfonyl_((C≤8)), or a substituted version of any of            these groups; or

—X₂—(CH₂)_(p)—R_(4′″);

-   -   wherein:        -   X₂ is arenediyl_((C≤12)), substituted arenediyl_((C≤12)),            heterocycloalkanediyl_((C≤12)), substituted            heterocycloalkanediyl_((C≤12)), heteroarenediyl_((C≤12)), or            substituted heteroarenediyl_((C≤12));        -   p is 0, 1, 2, 3, or 4; and        -   R_(4′″) is alkyl_((C≤8)), cycloalkyl_((C≤8)), aryl_((C≤8)),            heteroaryl_((C≤8)), heterocycloalkyl_((C≤8)), acyl_((C≤8)),            amido_((C≤8)), alkoxy_((C≤8)), acyloxy_((C≤8)),            —C(O)-alkoxy_((C≤8)), —C(O)-alkylamino_((C≤8)),            —C(O)-dialkyl-amino_((C≤8)), alkylsulfonyl_((C≤8)),            arylsulfonyl_((C≤8)), alkoxysulfonyl_((C≤8)), or a            substituted version of any of these groups; and    -   R₅ is amino, hydroxy, —OS(O)₂C₆H₄CH₃, alkyl_((C≤12)),        alkoxy_((C≤12)), cycloalkyl_((C≤12)), cycloalkoxy_((C≤12)),        aryl_((C≤12)), aralkyl_((C≤12)), heteroaryl_((C≤12)),        heteroaralkyl_((C≤12)), heterocycloalkyl_((C≤12)),        acyl_((C≤12)), acyloxy_((C≤12)), alkylamino_((C≤12)),        dialkylamino_((C≤12)), alkylsulfonylamino_((C≤12)), or a        substituted version of any of the last fourteen groups, or

—OY₁-A₁;

-   -   wherein:        -   Y₁ is alkanediyl_((C≤8)) or substituted alkanediyl_((C≤8));            and        -   A₁ is cycloalkyl_((C≤8)) or substituted cycloalkyl_((C≤8));            or

—Y₂—C(O)NR_(c)-A₂;

-   -   wherein:        -   Y₂ is arenediyl_((C≤8)) or substituted arenediyl_((C≤8));        -   R_(c) is hydrogen, alkyl_((C≤6)), or substituted            alkyl_((C≤6)); and        -   A₂ is aralkyl_((C≤12)) or substituted aralkyl_((C≤12)); or

-A₃R_(d);

-   -   wherein:        -   A₃ is —O— or —NR_(e)—, wherein            -   R_(e) is hydrogen, alkyl_((C≤6)), or substituted                alkyl_((C≤6)); and        -   R_(d) is acyl_((C≤12)), or substituted acyl_((C≤12));    -   provided that when carbon atoms 4 and 5 are joined by a double        bond, then R_(2′) and the hydrogen atom at carbon atom 5 are        absent;        or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is further defined as:

wherein:

-   -   the bond between carbon atoms 1 and 2 is an epoxidized double        bond or a double bond;    -   R₁ is cyano, heteroaryl_((C≤8)), substituted heteroaryl_((C≤8)),        —CF₃, or —C(O)R_(a); wherein:        -   R_(a) is hydroxy, amino, or alkoxy_((C≤8)),            alkylamino_((C≤8)), dialkylamino_((C≤8)),            alkylsulfonylamino_((C≤8)), or a substituted version of any            of these groups;    -   R₂ is hydrogen or alkyl_((C≤12)), cycloalkyl_((C≤12)),        alkenyl_((C≤12)), alkynyl_((C≤12)), aryl_((C≤12)),        aralkyl_((C≤12)), heteroaryl_((C≤12)), heteroaralkyl_((C≤12)),        acyl_((C≤12)), or a substituted version of any of these groups,        or -alkanediyl_((C≤8))-cycloalkyl_((C≤12)) or a substituted        version of this group;    -   R_(2′) is hydrogen, alkyl_((C≤12)), cycloalkyl_((C≤12)),        alkenyl_((C≤12)), alkynyl_((C≤12)), or a substituted version of        the last four groups;    -   R₃ is alkyl_((C≤12)), aryl_((C≤12)), aralkyl_((C≤12)), or a        substituted version of any of these groups;    -   R₄ is hydrogen, amino, alkyl_((C2-18)), substituted        alkyl_((C≤18)), cycloalkyl_((C≤18)), substituted        cycloalkyl_((C≤18)), aryl_((C≤18)), substituted aryl_((C≤18)),        aralkyl_((C≤18)), substituted aralkyl_((C≤18)),        heteroaryl_((C≤18)), substituted heteroaryl_((C≤18)),        heteroaralkyl_((C≤18)), substituted heteroaralkyl_((C≤18)),        heterocycloalkyl_((C≤18)), substituted        heterocycloalkyl_((C≤18)), alkylamino_((C≤18)), substituted        alkylamino_((C≤18)), dialkylamino_((C≤18)), substituted        dialkylamino_((C≤18)), alkylthio_((C≤18)), substituted        alkylthio_((C≤18)), amido_((C≤18)), substituted amido_((C≤18)),        or

—X₁—(CH₂)_(m)—R_(4′);

-   -   wherein:        -   X₁ is NR_(b), O, or S; wherein:            -   R_(b) is hydrogen, alkyl_((C≤6)), or substituted                alkyl_((C≤6));        -   m is 0, 1, 2, 3, or 4; and        -   R_(4′) is alkyl_((C≤12)), cycloalkyl_((C≤18)),            aryl_((C≤18)), aralkyl_((C≤18)), heteroaryl_((C≤18)),            heteroaralkyl_((C≤18)), heterocycloalkyl_((C≤18)), or a            substituted version of any of these groups, provided that            when X₁ is O, then R_(4′) is not methyl; or

-   -   wherein:        -   n is 0, 1, 2, 3, or 4; and        -   R_(4″) is —H, —OH, —F, —Cl, —Br, —I, —NH₂, —NO₂, —CN, —SH,            —S(O)₂OH, or —S(O)₂NH₂, or alkyl_((C≤8)),            cycloalkyl_((C≤8)), aryl_((C≤8)), heteroaryl_((C≤8)),            heterocycloalkyl_((C≤8)), acyl_((C≤8)), amido_((C≤8)),            alkoxy_((C≤8)), acyloxy_((C≤8)), alkylamino_((C≤8)),            dialkylamino_((C≤8)), —C(O)-alkoxy_((C≤8)),            —C(O)-alkylamino_((C≤8)), —C(O)-dialkyl-amino_((C≤8)),            alkylsulfonyl_((C≤8)), arylsulfonyl_((C≤8)),            alkoxysulfonyl_((C≤8)), or a substituted version of any of            these groups; or

—X₂—(CH₂)_(p)—R_(4′″);

-   -   wherein:        -   X₂ is arenediyl_((C≤12)), substituted arenediyl_((C≤12)),            heterocycloalkanediyl_((C≤12)), substituted            heterocycloalkanediyl_((C≤12)), heteroarenediyl_((C≤12)), or            substituted heteroarenediyl_((C≤12));        -   p is 0, 1, 2, 3, or 4; and        -   R_(4′″) is alkyl_((C≤8)), cycloalkyl_((C≤8)), aryl_((C≤8)),            heteroaryl_((C≤8)), heterocycloalkyl_((C≤8)), acyl_((C≤8)),            amido_((C≤8)), alkoxy_((C≤8)), acyloxy_((C≤8)),            —C(O)-alkoxy_((C≤8)), —C(O)-alkylamino_((C≤8)),            —C(O)-dialkyl-amino_((C≤8)), alkylsulfonyl_((C≤8)),            arylsulfonyl_((C≤8)), alkoxysulfonyl_((C≤8)), or a            substituted version of any of these groups; and    -   R₅ is amino, hydroxy, —OS(O)₂C₆H₄CH₃, alkyl_((C≤12)),        alkoxy_((C≤12)), cycloalkyl_((C≤12)), cycloalkoxy_((C≤12)),        aryl_((C≤12)), aralkyl_((C≤12)), heteroaryl_((C≤12)),        heterocycloalkyl_((C≤12)), acyl_((C≤12)), acyloxy_((C≤12)),        alkylamino_((C≤12)), dialkylamino_((C≤12)),        alkylsulfonylamino_((C≤12)), or a substituted version of any of        the last fourteen groups, or

—OY₁-A₁;

-   -   wherein:        -   Y₁ is alkanediyl_((C≤8)) or substituted alkanediyl_((C≤8));            and        -   A₁ is cycloalkyl_((C≤8)) or substituted cycloalkyl_((C≤8));            or

—Y₂—C(O)NR_(b)-A₂;

-   -   wherein:        -   Y₂ is arenediyl_((C≤8)) or substituted arenediyl_((C≤8));        -   R_(b) is hydrogen, alkyl_((C≤6)), or substituted            alkyl_((C≤6)); and        -   A₂ is aralkyl_((C≤12)) or substituted aralkyl_((C≤12)); or

-A₃R_(d);

-   -   wherein:        -   A₃ is —O— or —NR_(e)—, wherein            -   R_(e) is hydrogen, alkyl_((C≤6)), or substituted                alkyl_((C≤6)); and        -   R_(d) is acyl_((C≤12)), or substituted acyl_((C≤12));            or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is further defined as:

wherein:

-   -   the bond between carbon atoms 1 and 2 is an epoxidized double        bond or a double bond;    -   R₁ is cyano, heteroaryl_((C≤8)), substituted heteroaryl_((C≤8)),        —CF₃, or —C(O)R_(a); wherein:        -   R_(a) is hydroxy, amino, or alkoxy_((C≤8)),            alkylamino_((C≤8)), dialkylamino_((C≤8)),            alkylsulfonylamino_((C≤8)), or a substituted version of any            of these groups;    -   R₂ is hydrogen or alkyl_((C≤12)), cycloalkyl_((C≤12)),        alkenyl_((C≤12)), alkynyl_((C≤12)), aryl_((C≤12)),        aralkyl_((C≤12)), heteroaryl_((C≤12)), heteroaralkyl_((C≤12)),        acyl_((C≤12)), or a substituted version of any of these groups,        or -alkanediyl_((C≤8))-cycloalkyl_((C≤12)) or a substituted        version of this group;    -   R₃ is alkyl_((C≤12)), aryl_((C≤12)), aralkyl_((C≤12)), or a        substituted version of any of these groups;    -   R₄ is hydrogen, amino, alkyl_((C2-18)), substituted        alkyl_((C≤18)), cycloalkyl_((C≤18)), substituted        cycloalkyl_((C≤18)), aryl_((C≤18)), substituted aryl_((C≤18)),        aralkyl_((C≤18)), substituted aralkyl_((C≤18)),        heteroaryl_((C≤18)), substituted heteroaryl_((C≤18)),        heteroaralkyl_((C≤18)), substituted heteroaralkyl_((C≤18)),        heterocycloalkyl_((C≤18)), substituted        heterocycloalkyl_((C≤18)), alkylamino_((C≤18)), substituted        alkylamino_((C≤18)), dialkylamino_((C≤18)), substituted        dialkylamino_((C≤18)), alkylthio_((C≤18)), substituted        alkylthio_((C≤18)), amido_((C≤18)), substituted amido_((C≤18)),        or

—X₁—(CH₂)_(m)—R_(4′);

-   -   wherein:        -   X₁ is NR_(b), O, or S; wherein:            -   R_(b) is hydrogen, alkyl_((C≤6)), or substituted                alkyl_((C≤6));        -   m is 0, 1, 2, 3, or 4; and        -   R_(4′) is alkyl_((C≤12)), cycloalkyl_((C≤18)),            aryl_((C≤18)), aralkyl_((C≤18)), heteroaryl_((C≤18)),            heteroaralkyl_((C≤18)), heterocycloalkyl_((C≤18)), or a            substituted version of any of these groups, provided that            when X₁ is O, then R_(4′) is not methyl; or

wherein:

-   -   n is 0, 1, 2, 3, or 4; and    -   R_(4″) is —H, —OH, —F, —Cl, —Br, —I, —NH₂, —NO₂, —CN, —SH,        —S(O)₂OH, or —S(O)₂NH₂, or alkyl_((C≤8)), cycloalkyl_((C≤8)),        aryl_((C≤8)), heteroaryl_((C≤8)), heterocycloalkyl_((C≤8)),        acyl_((C≤8)), amido_((C≤8)), alkoxy_((C≤8)), acyloxy_((C≤8)),        alkylamino_((C≤8)), dialkylamino_((C≤8)), —C(O)-alkoxy_((C≤8)),        —C(O)-alkylamino_((C≤8)), —C(O)-dialkyl-amino_((C≤8)),        alkylsulfonyl_((C≤8)), arylsulfonyl_((C≤8)),        alkoxysulfonyl_((C≤8)), or a substituted version of any of these        groups; or

—X₂—(CH₂)_(p)—R_(4′″);

-   -   wherein:        -   X₂ is arenediyl_((C≤12)), substituted arenediyl_((C≤12)),            heterocycloalkanediyl_((C≤12)), substituted            heterocycloalkanediyl_((C≤12)), heteroarenediyl_((C≤12)), or            substituted heteroarenediyl_((C≤12));        -   p is 0, 1, 2, 3, or 4; and        -   R_(4′″) is alkyl_((C≤8)), cycloalkyl_((C≤8)), aryl_((C≤8)),            heteroaryl_((C≤8)), heterocycloalkyl_((C≤8)), acyl_((C≤8)),            amido_((C≤8)), alkoxy_((C≤8)), acyloxy_((C≤8)),            —C(O)-alkoxy_((C≤8)), —C(O)-alkylamino_((C≤8)),            —C(O)-dialkyl-amino_((C≤8)), alkylsulfonyl_((C≤8)),            arylsulfonyl_((C≤8)), alkoxysulfonyl_((C≤8)), or a            substituted version of any of these groups; and    -   R₅ is amino, hydroxy, —OS(O)₂C₆H₄CH₃, alkyl_((C≤12)),        alkoxy_((C≤12)), cycloalkyl_((C≤12)), cycloalkoxy_((C≤12)),        aryl_((C≤12)), aralkyl_((C≤12)), heteroaryl_((C≤12)),        heterocycloalkyl_((C≤12)), acyl_((C≤12)), acyloxy_((C≤12)),        alkylamino_((C≤12)), dialkylamino_((C≤12)),        alkylsulfonylamino_((C≤12)), or a substituted version of any of        the last fourteen groups, or

—OY₁-A₁;

-   -   wherein:        -   Y₁ is alkanediyl_((C≤8)) or substituted alkanediyl_((C≤8));            and        -   A₁ is cycloalkyl_((C≤8)) or substituted cycloalkyl_((C≤8));            or

—Y₂—C(O)NR_(b)-A₂;

-   -   wherein:        -   Y₂ is arenediyl_((C≤8)) or substituted arenediyl_((C≤8));        -   R_(b) is hydrogen, alkyl_((C≤6)), or substituted            alkyl_((C≤6)); and        -   A₂ is aralkyl_((C≤12)) or substituted aralkyl_((C≤12)); or

-A₃R_(d);

-   -   wherein:        -   A₃ is —O— or —NR_(e)—, wherein            -   R_(e) is hydrogen, alkyl_((C≤6)), or substituted                alkyl_((C≤6)); and        -   R_(d) is acyl_((C≤12)), or substituted acyl_((C≤12));            or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is further defined as:

wherein:

-   -   the bond between carbon atoms 1 and 2 is an epoxidized double        bond or a double bond;    -   R₁ is cyano, heteroaryl_((C≤8)), substituted heteroaryl_((C≤8)),        —CF₃, or —C(O)R_(a); wherein:        -   R_(a) is hydroxy, amino, or alkoxy_((C≤8)),            alkylamino_((C≤8)), dialkylamino_((C≤8)),            alkylsulfonylamino_((C≤8)), or a substituted version of any            of these groups;    -   R₂ is hydrogen or alkyl_((C≤12)), cycloalkyl_((C≤12)),        alkenyl_((C≤12)), alkynyl_((C≤12)), aryl_((C≤12)),        aralkyl_((C≤12)), heteroaryl_((C≤12)), heteroaralkyl_((C≤12)),        acyl_((C≤12)), or a substituted version of any of these groups,        or -alkanediyl_((C≤8))-cycloalkyl_((C≤12)) or a substituted        version of this group;    -   R₄ is hydrogen, amino, alkyl_((C2-18)), substituted        alkyl_((C≤18)), cycloalkyl_((C≤18)), substituted        cycloalkyl_((C≤18)), aryl_((C≤18)), substituted aryl_((C≤18)),        aralkyl_((C≤18)), substituted aralkyl_((C≤18)),        heteroaryl_((C≤18)), substituted heteroaryl_((C≤18)),        heteroaralkyl_((C≤18)), substituted heteroaralkyl_((C≤18)),        heterocycloalkyl_((C≤18)), substituted        heterocycloalkyl_((C≤18)), alkylamino_((C≤18)), substituted        alkylamino_((C≤18)), dialkylamino_((C≤18)), substituted        dialkylamino_((C≤18)), alkylthio_((C≤18)), substituted        alkylthio_((C≤18)), amido_((C≤18)), substituted amido_((C≤18)),        or

—X₁—(CH₂)_(m)—R_(4′);

wherein:

-   -   X₁ is NR_(b), O, or S; wherein:        -   R_(b) is hydrogen, alkyl_((C≤6)), or substituted            alkyl_((C≤6));    -   m is 0, 1, 2, 3, or 4; and    -   R_(4′) is alkyl_((C≤12)), cycloalkyl_((C≤18)), aryl_((C≤18)),        aralkyl_((C≤18)), heteroaryl_((C≤18)), heteroaralkyl_((C≤18)),        heterocycloalkyl_((C≤18)), or a substituted version of any of        these groups, provided that when X₁ is O, then R_(4′) is not        methyl; or

wherein:

-   -   n is 0, 1, 2, 3, or 4; and    -   R_(4″) is —H, —OH, —F, —Cl, —Br, —I, —NH₂, —NO₂, —CN, —SH,        —S(O)₂OH, or —S(O)₂NH₂, or alkyl_((C≤8)), cycloalkyl_((C≤8)),        aryl_((C≤8)), heteroaryl_((C≤8)), heterocycloalkyl_((C≤8)),        acyl_((C≤8)), amido_((C≤8)), alkoxy_((C≤8)), acyloxy_((C≤8)),        alkylamino_((C≤8)), dialkylamino_((C≤8)), —C(O)-alkoxy_((C≤8)),        —C(O)-alkylamino_((C≤8)), —C(O)-dialkyl-amino_((C≤8)),        alkylsulfonyl_((C≤8)), arylsulfonyl_((C≤8)),        alkoxysulfonyl_((C≤8)), or a substituted version of any of these        groups; or

—X₂—(CH₂)_(p)—R_(4′″);

-   -   wherein:        -   X₂ is arenediyl_((C≤12)), substituted arenediyl_((C≤12)),            heterocycloalkanediyl_((C≤12)), substituted            heterocycloalkanediyl_((C≤12)), heteroarenediyl_((C≤12)), or            substituted heteroarenediyl_((C≤12));        -   p is 0, 1, 2, 3, or 4; and        -   R_(4′″) is alkyl_((C≤8)), cycloalkyl_((C≤8)), aryl_((C≤8)),            heteroaryl_((C≤8)), heterocycloalkyl_((C≤8)), acyl_((C≤8)),            amido_((C≤8)), alkoxy_((C≤8)), acyloxy_((C≤8)),            —C(O)-alkoxy_((C≤8)), —C(O)-alkylamino_((C≤8)),            —C(O)-dialkyl-amino_((C≤8)), alkylsulfonyl_((C≤8)),            arylsulfonyl_((C≤8)), alkoxysulfonyl_((C≤8)), or a            substituted version of any of these groups; and    -   R₅ is amino, hydroxy, —OS(O)₂C₆H₄CH₃, alkyl_((C≤12)),        alkoxy_((C≤12)), cycloalkyl_((C≤12)), cycloalkoxy_((C≤12)),        aryl_((C≤12)), aralkyl_((C≤12)), heteroaryl_((C≤12)),        heterocycloalkyl_((C≤12)), acyl_((C≤12)), acyloxy_((C≤12)),        alkylamino_((C≤12)), dialkylamino_((C≤12)),        alkylsulfonylamino_((C≤12)), or a substituted version of any of        the last fourteen groups, or

—OY₁-A₁;

-   -   wherein:        -   Y₁ is alkanediyl_((C≤8)) or substituted alkanediyl_((C≤8));            and        -   A₁ is cycloalkyl_((C≤8)) or substituted cycloalkyl_((C≤8));            or

—Y₂—C(O)NR_(b)-A₂;

-   -   wherein:        -   Y₂ is arenediyl_((C≤8)) or substituted arenediyl_((C≤8));        -   R_(b) is hydrogen, alkyl_((C≤6)), or substituted            alkyl_((C≤6)); and        -   A₂ is aralkyl_((C≤12)) or substituted aralkyl_((C≤12)); or

-A₃R_(d);

-   -   wherein:        -   A₃ is —O— or —NR_(e)—, wherein            -   R_(e) is hydrogen, alkyl_((C≤6)), or substituted                alkyl_((C≤6)); and        -   R_(d) is acyl_((C≤12)), or substituted acyl_((C≤12));            or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is further defined as:

wherein:

-   -   R₁ is cyano, heteroaryl_((C≤8)), substituted heteroaryl_((C≤8)),        —CF₃, or —C(O)R_(a); wherein:        -   R_(a) is hydroxy, amino, or alkoxy_((C≤8)),            alkylamino_((C≤8)), dialkylamino_((C≤8)),            alkylsulfonylamino_((C≤8)), or a substituted version of any            of these groups;    -   R₂ is hydrogen or alkyl_((C≤12)), cycloalkyl_((C≤12)),        alkenyl_((C≤12)), alkynyl_((C≤12)), aryl_((C≤12)),        aralkyl_((C≤12)), heteroaryl_((C≤12)), heteroaralkyl_((C≤12)),        acyl_((C≤12)), or a substituted version of any of these groups,        or -alkanediyl_((C≤8))-cycloalkyl_((C≤12)) or a substituted        version of this group;    -   R₄ is hydrogen, amino, alkyl_((C2-18)), substituted        alkyl_((C≤18)), cycloalkyl_((C≤18)), substituted        cycloalkyl_((C≤18)), aryl_((C≤18)), substituted aryl_((C≤18)),        aralkyl_((C≤18)), substituted aralkyl_((C≤18)),        heteroaryl_((C≤18)), substituted heteroaryl_((C≤18)),        heteroaralkyl_((C≤18)), substituted heteroaralkyl_((C≤18)),        heterocycloalkyl_((C≤18)), substituted        heterocycloalkyl_((C≤18)), alkylamino_((C≤18)), substituted        alkylamino_((C≤18)), dialkylamino_((C≤18)), substituted        dialkylamino_((C≤18)), alkylthio_((C≤18)), substituted        alkylthio_((C≤18)), amido_((C≤18)), substituted amido_((C≤18)),        or

—X₁—(CH₂)_(m)—R_(4′);

-   -   wherein:        -   X₁ is NR_(b), O, or S; wherein:            -   R_(b) is hydrogen, alkyl_((C≤6)), or substituted                alkyl_((C≤6));    -   m is 0, 1, 2, 3, or 4; and    -   R_(4′) is alkyl_((C≤12)), cycloalkyl_((C≤18)), aryl_((C≤18)),        aralkyl_((C≤18)), heteroaryl_((C≤18)), heteroaralkyl_((C≤18)),        heterocycloalkyl_((C≤18)), or a substituted version of any of        these groups, provided that when X₁ is O, then R_(4′) is not        methyl; or

-   -   wherein:        -   n is 0, 1, 2, 3, or 4; and        -   R_(4″) is —H, —OH, —F, —Cl, —Br, —I, —NH₂, —NO₂, —CN, —SH,            —S(O)₂OH, or —S(O)₂NH₂, or alkyl_((C≤8)),            cycloalkyl_((C≤8)), aryl_((C≤8)), heteroaryl_((C≤8)),            heterocycloalkyl_((C≤8)), acyl_((C≤8)), amido_((C≤8)),            alkoxy_((C≤8)), acyloxy_((C≤8)), alkylamino_((C≤8)),            dialkylamino_((C≤8)), —C(O)-alkoxy_((C≤8)),            —C(O)-alkylamino_((C≤8)), —C(O)-dialkyl-amino_((C≤8)),            alkylsulfonyl_((C≤8)), arylsulfonyl_((C≤8)),            alkoxysulfonyl_((C≤8)), or a substituted version of any of            these groups; or

—X₂—(CH₂)_(p)—R_(4′″);

-   -   wherein:        -   X₂ is arenediyl_((C≤12)), substituted arenediyl_((C≤12)),            heterocycloalkanediyl_((C≤12)), substituted            heterocycloalkanediyl_((C≤12)), heteroarenediyl_((C≤12)), or            substituted heteroarenediyl_((C≤12));        -   p is 0, 1, 2, 3, or 4; and        -   R_(4′″) is alkyl_((C≤8)), cycloalkyl_((C≤8)), aryl_((C≤8)),            heteroaryl_((C≤8)), heterocycloalkyl_((C≤8)), acyl_((C≤8)),            amido_((C≤8)), alkoxy_((C≤8)), acyloxy_((C≤8)),            —C(O)-alkoxy_((C≤8)), —C(O)-alkylamino_((C≤8)),            —C(O)-dialkyl-amino_((C≤8)), alkylsulfonyl_((C≤8)),            arylsulfonyl_((C≤8)), alkoxysulfonyl_((C≤8)), or a            substituted version of any of these groups; and    -   R₅ is amino, hydroxy, —OS(O)₂C₆H₄CH₃, alkyl_((C≤12)),        alkoxy_((C≤12)), cycloalkyl_((C≤12)), cycloalkoxy_((C≤12)),        aryl_((C≤12)), aralkyl_((C≤12)), heteroaryl_((C≤12)),        heterocycloalkyl_((C≤12)), acyl_((C≤12)), acyloxy_((C≤12)),        alkylamino_((C≤12)), dialkylamino_((C≤12)),        alkylsulfonylamino_((C≤12)), or a substituted version of any of        the last fourteen groups, or

—OY₁-A₁;

-   -   wherein:        -   Y₁ is alkanediyl_((C≤8)) or substituted alkanediyl_((C≤8));            and        -   A₁ is cycloalkyl_((C≤8)) or substituted cycloalkyl_((C≤8));            or

—Y₂—C(O)NR_(b)-A₂;

-   -   wherein:        -   Y₂ is arenediyl_((C≤8)) or substituted arenediyl_((C≤8));        -   R_(b) is hydrogen, alkyl_((C≤6)), or substituted            alkyl_((C≤6)); and        -   A₂ is aralkyl_((C≤12)) or substituted aralkyl_((C≤12)); or

-A₃R_(d);

-   -   wherein:        -   A₃ is —O— or —NR_(e)—, wherein            -   R_(e) is hydrogen, alkyl_((C≤6)), or substituted                alkyl_((C≤6)); and        -   R_(d) is acyl_((C≤12)), or substituted acyl_((C≤12));            or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is further defined as:

wherein:

-   -   R₂ is hydrogen or alkyl_((C≤12)), cycloalkyl_((C≤12)),        alkenyl_((C≤12)), alkynyl_((C≤12)), aryl_((C≤12)),        aralkyl_((C≤12)), heteroaryl_((C≤12)), heteroaralkyl_((C≤12)),        acyl_((C≤12)), or a substituted version of any of these groups,        or -alkanediyl_((C≤8))-cycloalkyl_((C≤12)) or a substituted        version of this group;    -   R₄ is hydrogen, amino, alkyl_((C2-18)), substituted        alkyl_((C≤18)), cycloalkyl_((C≤18)), substituted        cycloalkyl_((C≤18)), aryl_((C≤18)), substituted aryl_((C≤18)),        aralkyl_((C≤18)), substituted aralkyl_((C≤18)),        heteroaryl_((C≤18)), substituted heteroaryl_((C≤18)),        heteroaralkyl_((C≤18)), substituted heteroaralkyl_((C≤18)),        heterocycloalkyl_((C≤18)), substituted        heterocycloalkyl_((C≤18)), alkylamino_((C≤18)), substituted        alkylamino_((C≤18)), dialkylamino_((C≤18)), substituted        dialkylamino_((C≤18)), alkylthio_((C≤18)), substituted        alkylthio_((C≤18)), amido_((C≤18)), substituted amido_((C≤18)),        or

—X₁—(CF₁₂)_(m)—R_(4′);

-   -   wherein:        -   X₁ is NR_(b), O, or S; wherein:            -   R_(b) is hydrogen, alkyl_((C≤6)), or substituted                alkyl_((C≤6));        -   m is 0, 1, 2, 3, or 4; and        -   R_(4′) is alkyl_((C≤12)), cycloalkyl_((C≤18)),            aryl_((C≤18)), aralkyl_((C≤18)), heteroaryl_((C≤18)),            heteroaralkyl_((C≤18)), heterocycloalkyl_((C≤18)), or a            substituted version of any of these groups, provided that            when X₁ is O, then R_(4′) is not methyl; or

-   -   wherein:        -   n is 0, 1, 2, 3, or 4; and        -   R_(4″) is —H, —OH, —F, —Cl, —Br, —I, —NH₂, —NO₂, —CN, —SH,            —S(O)₂OH, or —S(O)₂NH₂, or alkyl_((C≤8)),            cycloalkyl_((C≤8)), aryl_((C≤8)), heteroaryl_((C≤8)),            heterocycloalkyl_((C≤8)), acyl_((C≤8)), amido_((C≤8)),            alkoxy_((C≤8)), acyloxy_((C≤8)), alkylamino_((C≤8)),            dialkylamino_((C≤8)), —C(O)-alkoxy_((C≤8)),            —C(O)-alkylamino_((C≤8)), —C(O)-dialkyl-amino_((C≤8)),            alkylsulfonyl_((C≤8)), arylsulfonyl_((C≤8)),            alkoxysulfonyl_((C≤8)), or a substituted version of any of            these groups; or

—X₂—(CH₂)_(p)—R_(4′″);

-   -   wherein:        -   X₂ is arenediyl_((C≤12)), substituted arenediyl_((C≤12)),            heterocycloalkanediyl_((C≤12)), substituted            heterocycloalkanediyl_((C≤12)), heteroarenediyl_((C≤12)), or            substituted heteroarenediyl_((C≤12));        -   p is 0, 1, 2, 3, or 4; and        -   R_(4′″) is alkyl_((C≤8)), cycloalkyl_((C≤8)), aryl_((C≤8)),            heteroaryl_((C≤8)), heterocycloalkyl_((C≤8)), acyl_((C≤8)),            amido_((C≤8)), alkoxy_((C≤8)), acyloxy_((C≤8)),            —C(O)-alkoxy_((C≤8)), —C(O)-alkylamino_((C≤8)),            —C(O)-dialkyl-amino_((C≤8)), alkylsulfonyl_((C≤8)),            arylsulfonyl_((C≤8)), alkoxysulfonyl_((C≤8)), or a            substituted version of any of these groups; and    -   R₅ is amino, hydroxy, —OS(O)₂C₆H₄CH₃, alkyl_((C≤12)),        alkoxy_((C≤12)), cycloalkyl_((C≤12)), cycloalkoxy_((C≤12)),        aryl_((C≤12)), aralkyl_((C≤12)), heteroaryl_((C≤12)),        heterocycloalkyl_((C≤12)), acyl_((C≤12)), acyloxy_((C≤12)),        alkylamino_((C≤12)), dialkylamino_((C≤12)),        alkylsulfonylamino_((C≤12)), or a substituted version of any of        the last fourteen groups, or

—OY₁-A₁;

-   -   wherein:        -   Y₁ is alkanediyl_((C≤8)) or substituted alkanediyl_((C≤8));            and        -   A₁ is cycloalkyl_((C≤8)) or substituted cycloalkyl_((C≤8));            or

—Y₂—C(O)NR_(b)-A₂;

-   -   wherein:        -   Y₂ is arenediyl_((C≤8)) or substituted arenediyl_((C≤8));        -   R_(b) is hydrogen, alkyl_((C≤6)), or substituted            alkyl_((C≤6)); and        -   A₂ is aralkyl_((C≤12)) or substituted aralkyl_((C≤12)); or

-A₃R_(d);

-   -   wherein:        -   A₃ is —O— or —NR_(e)—, wherein            -   R_(e) is hydrogen, alkyl_((C≤6)), or substituted                alkyl_((C≤6)); and        -   R_(d) is acyl_((C≤12)), or substituted acyl_((C≤12));            or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is further defined as:

wherein:

-   -   R₂ is hydrogen, alkyl_((C≤12)), or substituted alkyl_((C≤12));    -   R₄ is heteroaryl_((C≤18)) or substituted heteroaryl_((C≤18));        and    -   R₅ is aryl_((C≤12)) or substituted aryl_((C≤12));        or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is further defined as:

wherein:

R₂ is alkyl_((C≤12)) or substituted alkyl_((C≤12));

HetAr is heteroaryl_((C≤18)) or substituted heteroaryl_((C≤18)); and

Ar is aryl_((C≤12)) or substituted aryl_((C≤12));

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is further defined as:

wherein:

R₄ is heteroaryl_((C≤18)) or substituted heteroaryl_((C≤18)); and

R₅ is aryl_((C≤12)) or substituted aryl_((C≤12));

or a pharmaceutically acceptable salt thereof.

In some embodiments, the inverse agonist is a compound of the formula:

wherein:

-   -   the bond between carbon atoms 1 and 2 is an epoxidized double        bond or a double bond;    -   the bond between carbon atoms 4 and 5 is a single bond or a        double bond;    -   a is 0, 1, or 2;    -   R₁ is cyano, heteroaryl_((C≤8)), substituted heteroaryl_((C≤8)),        —CF₃, or —C(O)R_(a); wherein:        -   R_(a) is hydroxy, amino, or alkoxy_((C≤8)),            alkylamino_((C≤8)), dialkylamino_((C≤8)),            alkylsulfonylamino_((C≤8)), or a substituted version of any            of these groups;    -   R₂ is hydrogen, alkyl_((C≤12)), cycloalkyl_((C≤12)),        alkenyl_((C≤12)), alkynyl_((C≤12)), or a substituted version of        the last four groups, or -alkanediyl_((C≤8))-cycloalkyl_((C≤12))        or a substituted version of this group;    -   R_(2′) is absent, hydrogen, alkyl_((C≤12)), cycloalkyl_((C≤12)),        alkenyl_((C≤12)), alkynyl_((C≤12)), or a substituted version of        the last four groups, provided that when the bond between carbon        atoms 4 and 5 is a double bond then R_(2′) is absent;    -   R₃ is alkyl_((C≤12)), aryl_((C≤12)), aralkyl_((C≤12)), or a        substituted version of any of these groups;    -   R₄ is cycloalkyl_((C≤18)), substituted cycloalkyl_((C≤18)),        heteroaryl_((C≤18)), substituted heteroaryl_((C≤18)),        heterocycloalkyl_((C≤18)), substituted        heterocycloalkyl_((C≤18)), or

—X₁—(CH₂)_(m)—R_(4′);

-   -   wherein:        -   X₁ is NR_(b), O, or S; wherein:            -   R_(b) is hydrogen, alkyl_((C≤6)), or substituted                alkyl_((C≤6));        -   m is 0, 1, 2, 3, or 4; and        -   R_(4′) is cycloalkyl_((C≤18)), aryl_((C≤18)),            aralkyl_((C≤18)), heteroaryl_((C≤18)),            heteroaralkyl_((C≤18)), heterocycloalkyl_((C≤18)), or a            substituted version of any of these groups; or

-   -   wherein:        -   n is 0, 1, 2, 3, or 4; and        -   R_(4″) is —H, —OH, —F, —Cl, —Br, —I, —NH₂, —NO₂, —CN, —SH,            —S(O)₂OH, or —S(O)₂NH₂, or alkyl_((C≤8)),            cycloalkyl_((C≤8)), aryl_((C≤8)), heteroaryl_((C≤8)),            heterocycloalkyl_((C≤8)), acyl_((C≤8)), amido_((C≤8)),            alkoxy_((C≤8)), acyloxy_((C≤8)), alkylamino_((C≤8)),            dialkylamino_((C≤8)), —C(O)-alkoxy_((C≤8)),            —C(O)-alkylamino_((C≤8)), —C(O)-dialkyl-amino_((C≤8)),            alkylsulfonyl_((C≤8)), arylsulfonyl_((C≤8)),            alkoxysulfonyl_((C≤8)), or a substituted version of any of            these groups; or

—X₂—(CH₂)_(p)—R_(4′″);

-   -   wherein:        -   X₂ is arenediyl_((C≤12)), substituted arenediyl_((C≤12)),            heterocycloalkyldiyl_((C≤12)), substituted            heterocycloalkyldiyl_((C≤12)), heteroarenediyl_((C≤12)), or            substituted heteroarenediyl_((C≤12));        -   p is 0, 1, 2, 3, or 4; and        -   R_(4′″) is alkyl_((C≤8)), cycloalkyl_((C≤8)), aryl_((C≤8)),            heteroaryl_((C≤8)), heterocycloalkyl_((C≤8)), acyl_((C≤8)),            alkoxy_((C≤8)), acyloxy_((C≤8)), —C(O)-alkoxy_((C≤8)),            —C(O)-alkylamino_((C≤8)), —C(O)-dialkyl-amino_((C≤8)),            alkylsulfonyl_((C≤8)), arylsulfonyl_((C≤8)),            alkoxysulfonyl_((C≤8)), or a substituted version of any of            these groups; and    -   R₅ is cycloalkoxy_((C≤12)), aryl_((C≤12)), heteroaryl_((C≤12)),        or a substituted version of any of the last three groups, or

—OY₁-A₁;

-   -   wherein:        -   Y₁ is alkanediyl_((C≤8)) or substituted alkanediyl_((C≤8));            and        -   A₁ is cycloalkyl_((C≤8)) or substituted cycloalkyl_((C≤8));            or    -   provided that when carbon atoms 4 and 5 are joined by a double        bond, then R_(2′) and the hydrogen atom at carbon atom 5 are        absent;        or a pharmaceutically acceptable salt thereof.

In some embodiments, the bond between carbon atom 1 and carbon atom 2 isan epoxidized double bond. In other embodiments, the bond between carbonatom 1 and carbon atom 2 is a double bond. In some embodiments, the bondbetween carbon atom 4 and carbon atom 5 is a single bond. In otherembodiments, the bond between carbon atom 4 and carbon atom 5 is adouble bond. In some embodiments, a is 1. In other embodiments, a is 0.In still other embodiments, a is 2. In some embodiments, R₁ is cyano. Insome embodiments, R₂ is alkyl_((C≤12)), alkenyl_((C≤12)), or asubstituted version of either of these groups. In further embodiments,R₂ is alkyl_((C≤12)) or substituted alkyl_((C≤12)). In still furtherembodiments, R₂ is alkyl_((C≤12)), such as methyl, ethyl, or propyl. Insome embodiments, R₂ is methyl. In other embodiments, R₂ is substitutedalkyl_((C≤12)), such as 3-hydroxypropyl. In still other embodiments, R₂is alkenyl_((C≤12)) or substituted alkenyl_((C≤12)). In furtherembodiments, R₂ is alkenyl_((C≤12)), such as 2-propenyl or2-methyl-prop-2-enyl. In some embodiments, R_(2′) is hydrogen. In otherembodiments, R_(2′) is alkyl_((C≤12)) or substituted alkyl_((C≤12)). Infurther embodiments, R_(2′) is alkyl_((C≤12)), such as methyl. In someembodiments, R₃ is alkyl_((C≤12)), aryl_((C≤12)), or a substitutedversion of either of these groups. In further embodiments, R₃ isalkyl_((C≤12)) or substituted alkyl_((C≤12)). In still furtherembodiments, R₃ is alkyl_((C≤12)), such as methyl, propyl, or isopentyl.In some embodiments, R₃ is methyl. In other embodiments, R₃ isaryl_((C≤12)) or substituted aryl_((C≤12)). In further embodiments, R₃is aryl_((C≤12)), such as phenyl.

In some embodiments, R₄ is alkyl_((C2-18)) or substitutedalkyl_((C2-18)). In other embodiments, R₄ is aryl_((C≤18)),heteroaryl_((C≤18)), or a substituted version of either of these groups.In further embodiments, R₄ is heteroaryl_((C≤18)) or substitutedheteroaryl_((C≤18)). In still further embodiments, R₄ is aheteroaryl_((C≤12)) or a substituted heteroaryl_((C≤12)) group whereinat least one of the heteroatoms in the aromatic ring is a nitrogen atom.In yet further embodiments, R₄ is heteroaryl_((C≤18)), such as3-pyridinyl, 4-pyridinyl, 4-(2-cycylopropyl)-pyridinyl,5-(2-cycylopropyl)-pyridinyl, 4-(2-morpholino)-pyridinyl,4-(2-phenyl)-pyridinyl, 3-(5-methyl)-pyridinyl, 3-(6-methyl)-pyridinyl,4-(2-methyl)-pyridinyl, 4-(3-methyl)-pyridinyl,3-pyrazolo[1,5-a]pyridinyl, 3-(N-methyl)-pyrrolo[2,3-b]pyridinyl,5-isoquinlinyl, 2-isoquinlinyl, 1-isoquinolinyl, 4-(2-phenyl)-pyridinyl,5-(2-phenyl)-pyridinyl, 3-(5-methyl)-pyridinyl, 4-(3-methyl)-pyridinyl,4-(3,5-dimethyl)-isoxazolyl, 4-(2-methyl)-pyridinyl,4-(3-methyl)-pyridinyl, 3-(4-methyl)-pyridinyl,4-(6-methyl)-pyrimidinyl, 6-(4-methyl)-pyrimidinyl, 4-pyridazinyl,2-quinazolinyl, 4-quinazolinyl, 2-quinolinyl, 3-quinolinyl,4-quinolinyl, 5-quinolinyl, 6-quinolinyl, 8-quinolinyl, 4-isoquinolinyl,3-(8-methyl)-quinolinyl, 3-(1-methyl)-quinolinyl,4-(2-methyl)-quinolinyl, 4-(2-isopropyl)-quinolinyl,4-(6-methyl)-quinolinyl, 4-(7-methyl)-quinolinyl,4-(8-methyl)-quinolinyl, 2-(N-methyl)-indolyl,5-(2,4-dimethyl)-thiazolyl, or 5-(3-methyl)-oxadizolyl. In otherembodiments, substituted heteroaryl_((C≤18)), such as4-(2-trifluoromethyl)-pyridinyl, 4-(3-fluoro)-pyridinyl,4-(2-methoxy)-pyridinyl, 4-(2-hydroxymethyl)-pyridinyl,4-(2-acetylamino)-pyridinyl, 4-(2-fluoromethyl)-pyridinyl,4-(2-acetamidylethyl)-pyridinyl, 4-(2-fluoromethyl)-quinolinyl,4-(2-acetoxymethyl)-quinolinyl, 4-(2-formyl)-quinolinyl,4-(6-fluoro)-quinolinyl, 4-(7-fluoro)-quinolinyl,4-(8-fluoro)-quinolinyl, 4-(6,8-difluoro)-quinolinyl,4-(6-fluoro-2-methyl)-quinolinyl, or 4-(8-fluoro-2-methyl)-quinolinyl.In still other embodiments, R₄ is aryl_((C≤12)) or substitutedaryl_((C≤12)). In further embodiments, R₄ is aryl_((C≤12)), such asphenyl. In yet other embodiments, R₄ is substituted aryl_((C≤12)), suchas 2-fluorophenyl or 4-trifluoromethylphenyl. In other embodiments, R₄is cycloalkyl_((C≤12)) or substituted cycloalkyl_((C≤12)). In furtherembodiments, R₄ is cycloalkyl_((C≤12)), such as cyclohexyl. In stillother embodiments, R₄ is:

wherein:

-   -   n is 0, 1, 2, 3, or 4; and    -   R_(4″) is —H, —OH, —F, —Cl, —Br, —I, —NH₂, —NO₂, —CN, —SH,        —S(O)₂OH, or —S(O)₂NH₂, or alkyl_((C≤8)), cycloalkyl_((C≤8)),        aryl_((C≤8)), heteroaryl_((C≤8)), heterocycloalkyl_((C≤8)),        acyl_((C≤8)), amido_((C≤8)), alkoxy_((C≤8)), acyloxy_((C≤8)),        alkylamino_((C≤8)), dialkylamino_((C≤8)), —C(O)-alkoxy_((C≤8)),        —C(O)-alkylamino_((C≤8)), —C(O)-dialkyl-amino_((C≤8)),        alkylsulfonyl_((C≤8)), arylsulfonyl_((C≤8)),        alkoxysulfonyl_((C≤8)), or a substituted version of any of these        groups.        In further embodiments, R₄ is:

In still further embodiments, R₄ is:

In yet other embodiments, R₄ is heterocycloalkyl_((C≤18)) or substitutedheterocycloalkyl_((C≤18)). In further embodiments, R₄ isheterocycloalkyl_((C≤12)), such as morpholinyl, 4-piperidinyl,3-(5-methyl-)1,2,3,6-tetrahydropyridinyl, or 4-N-methylpiperazinyl. Inother embodiments, R₄ is substituted heterocycloalkyl_((C≤12)), such asN-t-butyloxycarbonyl-4-piperidinyl, N-acetyl-4-piperidinyl,N-t-butyloxycarbonyl-5-methyl-1,2,3,6-tetrahydropyridinyl,N-acetyl-5-methyl-1,2,3,6-tetrahydropyridinyl, or 4-N-acetylpiperazinyl.In still other embodiments, R₄ is hydrogen. In yet other embodiments, R₄is —X₁—(CH₂)_(m)—R_(4′); wherein:

-   -   X₁ is NR_(b), O, or S; wherein:        -   R_(b) is hydrogen, alkyl_((C≤6)), or substituted            alkyl_((C≤6));    -   m is 0, 1, 2, 3, or 4; and    -   R_(4′) is alkyl_((C≤12)), cycloalkyl_((C≤18)), aryl_((C≤18)),        aralkyl_((C≤18)), heteroaryl_((C≤18)), heteroaralkyl_((C≤18)),        heterocycloalkyl_((C≤18)), or a substituted version of any of        these groups, provided that when X₁ is O, then R_(4′) is not        methyl.        In some embodiments, X₁ is NR_(b), wherein: R_(b) is hydrogen,        alkyl_((C≤6)), or substituted alkyl_((C≤6)). In further        embodiments, R_(b) is hydrogen. In some embodiments, m is 0        or 1. In some embodiments, m is 0. In some embodiments, R_(4′)        is cycloalkyl_((C≤18)), aryl_((C≤18)), aralkyl_((C≤18)),        heteroaryl_((C≤18)), heteroaralkyl_((C≤18)),        heterocycloalkyl_((C≤18)), or a substituted version of any of        these groups. In further embodiments, R_(4′) is        heteroaryl_((C≤12)) or substituted heteroaryl_((C≤12)). In still        further embodiments, R_(4′) is heteroaryl_((C≤12)), such as        4-pyridinyl. In other embodiments, R₄ is amino. In still other        embodiments, R₄ is amido_((C≤12)) or substituted amido_((C≤12)).        In further embodiments, R₄ is amido_((C≤12)), such as:

In other embodiments, R₄ is —X₂—(CH₂)_(p)— R_(4′″); wherein:

-   X₂ is arenediyl_((C≤12)), substituted arenediyl_((C≤12)),    heterocycloalkanediyl_((C≤12)), substituted    heterocycloalkanediyl_((C≤12)), heteroarenediyl_((C≤12)), or    substituted heteroarenediyl_((C≤12));-   p is 0, 1, 2, 3, or 4; and-   R_(4′″) is alkyl_((C≤8)), cycloalkyl_((C≤8)), aryl_((C≤8)),    heteroaryl_((C≤8)), heterocycloalkyl_((C≤8)), acyl_((C≤8)),    amido_((C≤8)), alkoxy_((C≤8)), acyloxy_((C≤8)),    —C(O)-alkoxy_((C≤8)), —C(O)-alkylamino_((C≤8)),    —C(O)-dialkylamino_((C≤8)), alkylsulfonyl_((C≤8)),    arylsulfonyl_((C≤8)), alkoxysulfonyl_((C≤8)), or a substituted    version of any of these groups.    In some embodiments, X₂ is heteroarenediyl_((C≤12)) or substituted    heteroarenediyl_((C≤12)). In further embodiments, X₂ is    heteroarenediyl_((C≤12)), such as pyridin-2,4-diyl or    pyridine-2,5-diyl. In still other embodiments, X₂ is    heterocycloalkanediyl_((C≤12)) or substituted    heterocycloalkanediyl_((C≤12)). In further embodiments, X₂ is    heterocycloalkanediyl_((C≤12)), such as piperidin-1,4-diyl,    piperazin-1,4-diyl, or 1,2,3,6-tetrahydropiperidin-1,5-diyl. In some    embodiments, p is 0, 1, or 2. In some embodiments, p is 0. In other    embodiments, p is 1. In still other embodiments, p is 2. In some    embodiments, R_(4′″) is acyl_((C≤8)) or substituted acyl_((C≤8)). In    further embodiments, R_(4′″) is acyl_((C≤8)), such as acetyl. In yet    other embodiments, R_(4′″) is substituted acyl_((C≤8)). In some    embodiments, R_(4′″) is carboxy. In other embodiments, R_(4′″) is    amido_((C≤8)) or substituted amido_((C≤8)). In further embodiments,    R_(4′″) is amido_((C≤8)), such as acetamidyl. In still other    embodiments, R_(4′″) is cycloalkyl_((C≤8)) or substituted    cycloalkyl_((C≤8)). In further embodiments, R_(4′″) is    cycloalkyl_((C≤8)), such as cyclopropyl. In yet other embodiments,    R_(4′″) is alkylsulfonyl_((C≤8)) or substituted    alkylsulfonyl_((C≤8)). In further embodiments, R_(4′″) is    alkylsulfonyl_((C≤8)), such as —S(O)₂CH₃ or —S(O)₂CH₂CH₃. In other    embodiments, R_(4′″) is —C(O)-alkoxy_((C≤8)), such as —C(O)OEt. In    still other embodiments, R_(4′″) is —C(O)-dialkylamino_((C≤8)), such    as —C(O)NMe₂.

In some embodiments, R₅ is aryl_((C≤12)), heteroaryl_((C≤12)), or asubstituted version of either of these groups. In further embodiments,R₅ is aryl_((C≤12)) or substituted aryl_((C≤12)). In still furtherembodiments, R₅ is aryl_((C≤12)), such as phenyl, 4-methylphenyl,3-isopropylphenyl, 4-isopropylphenyl, 1,3-biphenyl, or 1,4-biphenyl. Insome embodiments, R₅ further comprises one or more fluorine atoms. Insome embodiments, R₅ is substituted aryl_((C≤12)), such as R₅ is2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl,4-hydroxymethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl,4-methoxyphenyl, 4-chlorophenyl, or 3,4-dichlorophenyl. In otherembodiments, R₅ is cycloalkyl_((C≤12)), such as cyclopropyl, orsubstituted cycloalkyl_((C≤12)). In still other embodiments, R₅ iscycloalkoxy_((C≤12)), such as cyclobutyloxy, cyclopentyloxy, orcyclohexyloxy, or substituted cycloalkoxy_((C≤12)). In yet otherembodiments, R₅ is alkylamino_((C≤12)), dialkylamino_((C≤12)), or asubstituted version of either of these groups. In further embodiments,R₅ is dialkylamino_((C≤12)) or substituted dialkylamino_((C≤12)). Instill further embodiments, R₅ is dialkylamino_((C≤8)), such asdimethylamino, or substituted dialkylamino_((C≤8)). In otherembodiments, R₅ is alkylsulfonylamino_((C≤12)) or substitutedalkylsulfonylamino_((C≤12)). In further embodiments, R₆ ismethylsulfonylamino. In still other embodiments, R₅ is —OY₁-A;

wherein:

Y₁ is alkanediyl_((C≤8)) or substituted alkanediyl_((C≤8)); and

A₁ is cycloalkyl_((C≤8)) or substituted cycloalkyl_((C≤8)).

In some embodiments, Y₁ is methylene. In some embodiments, A₁ iscyclobutyl. In some embodiments, R₅ is:

In other embodiments, R₅ is —Y₂—C(O)NR_(c)-A₂; wherein:

Y₂ is arenediyl_((C≤8)) or substituted arenediyl_((C≤8));

R_(c) is hydrogen, alkyl_((C≤6)), or substituted alkyl_((C≤6)); and

A₂ is aralkyl_((C≤12)) or substituted aralkyl_((C≤12)).

In some embodiments, Y₂ is arenediyl_((C≤8)), such as benzenediyl. Insome embodiments, R_(c) is alkyl_((C≤6)), such as methyl. In someembodiments, A₂ is aralkyl_((C≤12)), such as benzyl. In still otherembodiments, R₅ is heteroaryl_((C≤12)) or substitutedheteroaryl_((C≤12)). In further embodiments, R₅ is heteroaryl_((C≤12)),such as 5-(3-methyl)-oxadiazolyl, 4-(3,5-dimethyl)-isoxazolyl, furanyl,benzofuranyl, 2-thiazolyl, 5-(2-methyl)-furanyl, 3-pyridinyl, or4-pyridinyl. In yet other embodiments, R₅ is hydroxy. In otherembodiments, R₅ is OS(O)₂C₆H₄CH₃. In still other embodiments, R₅ isheterocycloalkyl_((C≤12)) or substituted heterocycloalkyl_((C≤12)). Infurther embodiments, R₅ is heterocycloalkyl_((C≤12)), such aspyrrolidinyl. In yet other embodiments, R₅ is alkoxy_((C≤12)) orsubstituted alkoxy_((C≤12)). In further embodiments, R₅ isalkoxy_((C≤12)), such as methoxy or isopropoxy. In other embodiments, R₅is aralkyl_((C≤12)) or substituted aralkyl_((C≤12)). In furtherembodiments, R₅ is aralkyl_((C≤12)), such as benzyl.

In some embodiments, the compound is further defined as:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the inverse agonist is a compound of the formula:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the inverse agonist is a compound of the formula:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the inverse agonist is a compound of the formula:

wherein:

-   -   wherein the bond between carbon atoms 1 and 2 is an epoxidized        double bond or a double bond;    -   n is 0, 1, or 2;    -   R₁ is cyano, fluoro, —CF₃, or —C(O)R_(a), wherein:        -   R_(a) is hydroxy or amino; or            -   alkoxy_((C≤6)), alkylamino_((C≤6)),                dialkylamino_((C≤6)), or a substituted version of any of                these groups;    -   R₂ and R_(2′) are each independently hydrogen; or        -   alkyl_((C≤12)), cycloalkyl_((C≤12)), alkenyl_((C≤12)),            alkynyl_((C≤12)), aryl_((C≤18)), aralkyl_((C≤18)),            heteroaryl_((C≤18)), heteroaralkyl_((C≤18)), or a            substituted version of any of these groups; or        -   R₂ and R_(2′) are taken together and are alkanediyl_((C≤8)),            alkanediyl_((C≤8)), or a substituted version of either of            these groups;    -   R₃ is alkyl_((C≤12)), alkenyl_((C≤12)), aryl_((C≤12)),        aralkyl_((C≤12)), or a substituted version of any of these        groups;    -   R₄ and R₅ are each independently absent or hydrogen; or        -   alkyl_((C≤12)), cycloalkyl_((C≤12)),            heterocycloalkyl_((C≤12)), aryl_((C≤12)), aralkyl_((C≤12)),            heteroaryl_((C≤12)), heteroaralkyl_((C≤12)),            -arenediyl_((C≤12))-alkyl_((C≤12)),            -arenediyl_((C≤12))-aryl_((C≤12)),            -arenediyl_((C≤12))-heteroaryl_((C≤12)),            -arenediyl_((C≤12))-heterocycloalkyl_((C≤12)),            -arenediyl_((C≤12))-cycloalkyl_((C≤12)),            -heteroarenediyl_((C≤12))-alkyl_((C≤12)),            -heteroarenediyl_((C≤12))-aryl_((C≤12)),            -heteroarenediyl_((C≤12))-heteroaryl_((C≤12)),            -heteroarenediyl_((C≤12))-hetero-cycloalkyl_((C≤12)),            -heteroarenediyl_((C≤12))-cycloalkyl_((C≤12)),            -heterocyclo-alkanediyl_((C≤12))-aryl_((C≤12)),            -heterocycloalkanediyl_((C≤12))-heteroaryl_((C≤12)), or a            substituted version of any of these groups; or        -   a group of the formula:

-   -   wherein l and m are each 0, 1, 2, or 3;    -   R₆ is absent, hydrogen, or amino; or        -   alkylamino_((C≤12)), dialkylamino_((C≤12)),            cycloalkylamino_((C≤12)), dicycloalkylamino_((C≤12)),            alkyl(cycloalkyl)amino_((C≤12)), arylamino_((C≤12)),            diarylamino_((C≤12)), alkyl_((C≤12)), cycloalkyl_((C≤12)),            -alkanediyl_((C≤12))-cycloalkyl_((C≤12)),            -alkanediyl_((C≤18))-aralkoxy_((C≤18)),            heterocycloalkyl_((C≤12)), aryl_((C≤18)),            -arenediyl_((C≤12))-alkyl_((C≤12)), aralkyl_((C≤18)),            -arenediyl_((C≤18))-heterocycloalkyl_((C≤12)),            heteroaryl_((C≤18)),            -heteroarenediyl_((C≤12))-alkyl_((C≤12)),            heteroaralkyl_((C≤18)), acyl_((C≤12)), alkoxy_((C≤12)), or a            substituted version of any of these groups; and    -   X₁ and X₂ are each independently C or N, provided that X₂ is C        when R₆ is amino,        -   alkylamino_((C≤12)), dialkylamino_((C≤12)),            cycloalkylamino_((C≤12)), dicycloalkylamino_((C≤12)),            alkyl(cycloalkyl)amino_((C≤12)), arylamino_((C≤12)), or            diarylamino_((C≤12));            or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is further defined as:

wherein:

-   -   n is 0, 1, or 2;    -   R₁ is cyano, fluoro, —CF₃, or —C(O)R_(a), wherein        -   R_(a) is hydroxy or amino; or            -   alkoxy_((C≤6)), alkylamino_((C≤6)),                dialkylamino_((C≤6)), or a substituted version of any of                these groups;    -   R₂ and R_(2′) are each independently hydrogen; or        -   alkyl_((C≤12)), cycloalkyl_((C≤12)), alkenyl_((C≤12)),            alkynyl_((C≤12)), aryl_((C≤18)), aralkyl_((C≤18)),            heteroaryl_((C≤18)), heteroaralkyl_((C≤18)), or a            substituted version of any of these groups; or        -   R₂ and R_(2′) are taken together and are alkanediyl_((C≤8)),            alkanediyl_((C≤8)), or a substituted version of either of            these groups;    -   R₃ is alkyl_((C≤12)), alkenyl_((C≤12)), aryl_((C≤12)),        aralkyl_((C≤12)), or a substituted version of any of these        groups;    -   R₄ and R₅ are each independently absent or hydrogen; or        -   alkyl_((C≤12)), cycloalkyl_((C≤12)),            heterocycloalkyl_((C≤12)), aryl_((C≤12)), aralkyl_((C≤12)),            heteroaryl_((C≤12)), heteroaralkyl_((C≤12)),            -arenediyl_((C≤12))-alkyl_((C≤12)),            -arenediyl_((C≤12))-aryl_((C≤12)),            -arenediyl_((C≤12))-heteroaryl_((C≤12)),            -arenediyl_((C≤12))-heterocycloalkyl_((C≤12)),            -arenediyl_((C≤12))-cycloalkyl_((C≤12)),            -heteroarenediyl_((C≤12))-alkyl_((C≤12)),            -heteroarenediyl_((C≤12))-aryl_((C≤12)),            -heteroarenediyl_((C≤12))-heteroaryl_((C≤12)),            -heteroarenediyl_((C≤12))-hetero-cycloalkyl_((C≤12)),            -heteroarenediyl_((C≤12))-cycloalkyl_((C≤12)),            -heterocyclo-alkanediyl_((C≤12))-aryl_((C≤12)),            -heterocycloalkanediyl_((C≤12))-heteroaryl_((C≤12)), or a            substituted version of any of these groups; or        -   a group of the formula:

-   -   wherein l and m are each 0, 1, 2, or 3;    -   R₆ is absent, hydrogen, or amino; or        -   alkylamino_((C≤12)), dialkylamino_((C≤12)),            cycloalkylamino_((C≤12)), dicycloalkylamino_((C≤12)),            alkyl(cycloalkyl)amino_((C≤12)), arylamino_((C≤12)),            diarylamino_((C≤12)), alkyl_((C≤12)), cycloalkyl_((C≤12)),            -alkanediyl_((C≤12))-cycloalkyl_((C≤12)),            -alkanediyl_((C≤18))-aralkoxy_((C≤18)),            heterocycloalkyl_((C≤12)), aryl_((C≤18)),            -arenediyl_((C≤12))-alkyl_((C≤12)), aralkyl_((C≤18)),            -arenediyl_((C≤18))-heterocycloalkyl_((C≤12)),            heteroaryl_((C≤18)),            -heteroarenediyl_((C≤12))-alkyl_((C≤12)),            heteroaralkyl_((C≤18)), acyl_((C≤12)), alkoxy_((C≤12)), or a            substituted version of any of these groups; and    -   X₁ and X₂ are each independently C or N, provided that X₂ is C        when R₆ is amino, alkylamino_((C≤12)), dialkylamino_((C≤12)),        cycloalkylamino_((C≤12)), dicycloalkylamino_((C≤12)),        alkyl(cycloalkyl)amino_((C≤12)), arylamino_((C≤12)), or        diarylamino_((C≤12));        or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is further defined as:

wherein:

-   -   R₁ is cyano, fluoro, —CF₃, or —C(O)R_(a), wherein        -   R_(a) is hydroxy or amino; or            -   alkoxy_((C≤6)), alkylamino_((C≤6)),                dialkylamino_((C≤6)), or a substituted version of any of                these groups;    -   R₂ and R_(2′) are each independently hydrogen; or        -   alkyl_((C≤12)), cycloalkyl_((C≤12)), alkenyl_((C≤12)),            alkynyl_((C≤12)), aryl_((C≤18)), aralkyl_((C≤18)),            heteroaryl_((C≤18)), heteroaralkyl_((C≤18)), or a            substituted version of any of these groups; or        -   R₂ and R_(2′) are taken together and are alkanediyl_((C≤8)),            alkenediyl_((C≤8)), or a substituted version of either of            these groups;    -   R₃ is alkyl_((C≤12)), alkenyl_((C≤12)), aryl_((C≤12)),        aralkyl_((C≤12)), or a substituted version of any of these        groups;    -   R₄ and R₅ are each independently absent or hydrogen; or        -   alkyl_((C≤12)), cycloalkyl_((C≤12)),            heterocycloalkyl_((C≤12)), aryl_((C≤12)), aralkyl_((C≤12)),            heteroaryl_((C≤12)), heteroaralkyl_((C≤12)),            -arenediyl_((C≤12))-alkyl_((C≤12)),            -arenediyl_((C≤12))-aryl_((C≤12)),            -arenediyl_((C≤12))-heteroaryl_((C≤12)),            -arenediyl_((C≤12))-heterocycloalkyl_((C≤12)),            -arenediyl_((C≤12))-cycloalkyl_((C≤12)),            -heteroarenediyl_((C≤12))-alkyl_((C≤12)),            -heteroarenediyl_((C≤12))-aryl_((C≤12)),            -heteroarenediyl_((C≤12))-heteroaryl_((C≤12)),            -heteroarenediyl_((C≤12))-hetero-cycloalkyl_((C≤12)),            -heteroarenediyl_((C≤12))-cycloalkyl_((C≤12)),            -heterocyclo-alkanediyl_((C≤12))-aryl_((C≤12)),            -heterocycloalkanediyl_((C≤12))-heteroaryl_((C≤12)), or a            substituted version of any of these groups; or        -   a group of the formula:

-   -   wherein l and m are each 0, 1, 2, or 3;    -   R₆ is absent, hydrogen, or amino; or        -   alkylamino_((C≤12)), dialkylamino_((C≤12)),            cycloalkylamino_((C≤12)), dicycloalkylamino_((C≤12)),            alkyl(cycloalkyl)amino_((C≤12)), arylamino_((C≤12)),            diarylamino_((C≤12)), alkyl_((C≤12)), cycloalkyl_((C≤12)),            -alkanediyl_((C≤12))-cycloalkyl_((C≤12)),            -alkanediyl_((C≤18))-aralkoxy_((C≤18)),            heterocycloalkyl_((C≤12)), aryl_((C≤18)),            -arenediyl_((C≤12))-alkyl_((C≤12)), aralkyl_((C≤18)),            -arenediyl_((C≤18))-heterocycloalkyl_((C≤12)),            heteroaryl_((C≤18)),            -heteroarenediyl_((C≤12))-alkyl_((C≤12)),            heteroaralkyl_((C≤18)), acyl_((C≤12)), alkoxy_((C≤12)), or a            substituted version of any of these groups; and    -   X₁ and X₂ are each independently C or N, provided that X₂ is C        when R₆ is amino, alkylamino_((C≤12)), dialkylamino_((C≤12)),        cycloalkylamino_((C≤12)), dicycloalkylamino_((C≤12)),        alkyl(cycloalkyl)amino_((C≤12)), arylamino_((C≤12)), or        diarylamino_((C≤12));        or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is further defined as:

wherein:

-   -   R₁ is cyano, fluoro, —CF₃, or —C(O)R_(a), wherein        -   R_(a) is hydroxy or amino; or            -   alkoxy_((C≤6)), alkylamino_((C≤6)),                dialkylamino_((C≤6)), or a substituted version of any of                these groups;    -   R₂ and R_(2′) are each independently hydrogen; or        -   alkyl_((C≤12)), cycloalkyl_((C≤12)), alkenyl_((C≤12)),            alkynyl_((C≤12)), aryl_((C≤18)), aralkyl_((C≤18)),            heteroaryl_((C≤18)), heteroaralkyl_((C≤18)), or a            substituted version of any of these groups; or        -   R₂ and R_(2′) are taken together and are alkanediyl_((C≤8)),            alkenediyl_((C≤8)), or a substituted version of either of            these groups;    -   R₄ and R₅ are each independently absent or hydrogen; or        -   alkyl_((C≤12)), cycloalkyl_((C≤12)),            heterocycloalkyl_((C≤12)), aryl_((C≤12)), aralkyl_((C≤12)),            heteroaryl_((C≤12)), heteroaralkyl_((C≤12)),            -arenediyl_((C≤12))-alkyl_((C≤12)),            -arenediyl_((C≤12))-aryl_((C≤12)),            -arenediyl_((C≤12))-heteroaryl_((C≤12)),            -arenediyl_((C≤18))-heterocycloalkyl_((C≤12)),            -arenediyl_((C≤12))-cycloalkyl_((C≤12)),            -heteroarenediyl_((C≤12))-alkyl_((C≤12)),            -heteroarenediyl_((C≤12))-aryl_((C≤12)),            -heteroarenediyl_((C≤12))-heteroaryl_((C≤12)),            -heteroarenediyl_((C≤12))-hetero-cycloalkyl_((C≤12)),            -heteroarenediyl_((C≤12))-cycloalkyl_((C≤12)),            -heterocycloalkanediyl_((C≤12))-aryl_((C≤12)),            -heterocycloalkanediyl_((C≤12))-heteroaryl_((C≤12)), or a            substituted version of any of these groups; or        -   a group of the formula:

-   -   wherein l and m are each 0, 1, 2, or 3;    -   R₆ is absent, hydrogen, or amino; or        -   alkylamino_((C≤12)), dialkylamino_((C≤12)),            cycloalkylamino_((C≤12)), dicycloalkylamino_((C≤12)),            alkyl(cycloalkyl)amino_((C≤12)), arylamino_((C≤12)),            diarylamino_((C≤12)), alkyl_((C≤12)), cycloalkyl_((C≤12)),            -alkanediyl_((C≤12))-cycloalkyl_((C≤12)),            -alkanediyl_((C≤18))-aralkoxy_((C≤18)),            heterocycloalkyl_((C≤12)), aryl_((C≤18)),            -arenediyl_((C≤12))-alkyl_((C≤12)), aralkyl_((C≤18)),            -arenediyl_((C≤18))-heterocycloalkyl_((C≤12)),            heteroaryl_((C≤18)),            -heteroarenediyl_((C≤12))-alkyl_((C≤12)),            heteroaralkyl_((C≤18)), acyl_((C≤12)), alkoxy_((C≤12)), or a            substituted version of any of these groups; and    -   X₁ and X₂ are each independently C or N, provided that X₂ is C        when R₆ is amino, alkylamino_((C≤12)), dialkylamino_((C≤12)),        cycloalkylamino_((C≤12)), dicycloalkylamino_((C≤12)),        alkyl(cycloalkyl)amino_((C≤12)), arylamino_((C≤12)), or        diarylamino_((C≤12));        or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is further defined as:

wherein:

-   -   R₂ and R_(2′) are each independently hydrogen; or        -   alkyl_((C≤12)), cycloalkyl_((C≤12)), alkenyl_((C≤12)),            alkynyl_((C≤12)), aryl_((C≤18)), aralkyl_((C≤18)),            heteroaryl_((C≤18)), heteroaralkyl_((C≤18)), or a            substituted version of any of these groups; or        -   R₂ and R_(2′) are taken together and are alkanediyl_((C≤8)),            alkenediyl_((C≤8)), or a substituted version of either of            these groups;    -   R₄ and R₅ are each independently absent or hydrogen; or        -   alkyl_((C≤12)), cycloalkyl_((C≤12)),            heterocycloalkyl_((C≤12)), aryl_((C≤12)), aralkyl_((C≤12)),            heteroaryl_((C≤12)), heteroaralkyl_((C≤12)),            -arenediyl_((C≤12))-alkyl_((C≤12)),            -arenediyl_((C≤12))-aryl_((C≤12)),            -arenediyl_((C≤12))-heteroaryl_((C≤12)),            -arenediyl_((C≤12))-heterocycloalkyl_((C≤12)),            -arenediyl_((C≤12))-cycloalkyl_((C≤12)),            -heteroarenediyl_((C≤12))-alkyl_((C≤12)),            -heteroarenediyl_((C≤12))-aryl_((C≤12)),            -heteroarenediyl_((C≤12))-heteroaryl_((C≤12)),            -heteroarenediyl_((C≤12))-hetero-cycloalkyl_((C≤12)),            -heteroarenediyl_((C≤12))-cycloalkyl_((C≤12)),            -heterocyclo-alkanediyl_((C≤12))-aryl_((C≤12)),            -heterocycloalkanediyl_((C≤12))-heteroaryl_((C≤12)), or a            substituted version of any of these groups; or        -   a group of the formula:

-   -   wherein l and m are each 0, 1, 2, or 3;    -   R₆ is absent, hydrogen, or amino; or        -   alkylamino_((C≤12)), dialkylamino_((C≤12)),            cycloalkylamino_((C≤12)), dicycloalkylamino_((C≤12)),            alkyl(cycloalkyl)amino_((C≤12)), arylamino_((C≤12)),            diarylamino_((C≤12)), alkyl_((C≤12)), cycloalkyl_((C≤12)),            -alkanediyl_((C≤12))-cycloalkyl_((C≤12)),            -alkanediyl_((C≤18))-aralkoxy_((C≤18)),            heterocycloalkyl_((C≤12)), aryl_((C≤18)),            -arenediyl_((C≤12))-alkyl_((C≤12)), aralkyl_((C≤18)),            -arenediyl_((C≤18))-heterocycloalkyl_((C≤12)),            heteroaryl_((C≤18)),            -heteroarenediyl_((C≤12))-alkyl_((C≤12)),            heteroaralkyl_((C≤18)), acyl_((C≤12)), alkoxy_((C≤12)), or a            substituted version of any of these groups; and    -   X₁ and X₂ are each independently C or N, provided that X₂ is C        when R₆ is amino, alkylamino_((C≤12)), dialkylamino_((C≤12)),        cycloalkylamino_((C≤12)), dicycloalkylamino_((C≤12)),        alkyl(cycloalkyl)amino_((C≤12)), arylamino_((C≤12)), or        diarylamino_((C≤12));        or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is further defined as:

wherein:

-   -   R₂ and R_(2′) are each independently hydrogen; or        -   alkyl_((C≤12)), cycloalkyl_((C≤12)), alkenyl_((C≤12)),            alkynyl_((C≤12)), aryl_((C≤18)), aralkyl_((C≤18)),            heteroaryl_((C≤18)), heteroaralkyl_((C≤18)), or a            substituted version of any of these groups; or        -   R₂ and R_(2′) are taken together and are alkanediyl_((C≤8)),            alkenediyl_((C≤8)), or a substituted version of either of            these groups;    -   R₄ and R₅ are each independently absent, hydrogen; or        -   alkyl_((C≤12)), cycloalkyl_((C≤12)),            heterocycloalkyl_((C≤12)), aryl_((C≤12)), aralkyl_((C≤12)),            heteroaryl_((C≤12)), heteroaralkyl_((C≤12)),            -arenediyl_((C≤12))-alkyl_((C≤12)),            -arenediyl_((C≤12))-aryl_((C≤12)),            -arenediyl_((C≤12))-heteroaryl_((C≤12)),            -arenediyl_((C≤12))-heterocycloalkyl_((C≤12)),            -arenediyl_((C≤12))-cycloalkyl_((C≤12)),            -heteroarenediyl_((C≤12))-alkyl_((C≤12)),            -heteroarenediyl_((C≤12))-aryl_((C≤12)),            -heteroarenediyl_((C≤12))-heteroaryl_((C≤12)),            -heteroarenediyl_((C≤12))-hetero-cycloalkyl_((C≤12)),            -heteroarenediyl_((C≤12))-cycloalkyl_((C≤12)),            -heterocyclo-alkanediyl_((C≤12))-aryl_((C≤12)),            -heterocycloalkanediyl_((C≤12))-heteroaryl_((C≤12)), or a            substituted version of any of these groups; or        -   a group of the formula:

-   -   wherein l and m are each 0, 1, 2, or 3; and    -   R₆ is absent, hydrogen; or        -   alkylamino_((C≤12)), dialkylamino_((C≤12)),            cycloalkylamino_((C≤12)), dicycloalkylamino_((C≤12)),            alkyl(cycloalkyl)amino_((C≤12)), arylamino_((C≤12)),            diarylamino_((C≤12)), alkyl_((C≤12)), cycloalkyl_((C≤12)),            -alkanediyl_((C≤12))-cycloalkyl_((C≤12)),            -alkanediyl_((C≤18))-aralkoxy_((C≤18)),            heterocycloalkyl_((C≤12)), aryl_((C≤18)),            -arenediyl_((C≤12))-alkyl_((C≤12)), aralkyl_((C≤18)),            -arenediyl_((C≤18))-heterocycloalkyl_((C≤12)),            heteroaryl_((C≤18)),            -heteroarenediyl_((C≤12))-alkyl_((C≤12)),            heteroaralkyl_((C≤18)), acyl_((C≤12)), alkoxy_((C≤12)), or a            substituted version of any of these groups;            or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is further defined as:

wherein:

-   -   R₂ and R_(2′) are each independently hydrogen; or        -   alkyl_((C≤12)), cycloalkyl_((C≤12)), alkenyl_((C≤12)),            alkynyl_((C≤12)), aryl_((C≤18)), aralkyl_((C≤18)),            heteroaryl_((C≤18)), heteroaralkyl_((C≤18)), or a            substituted version of any of these groups; or    -   R₂ and R_(2′) are taken together and are alkanediyl_((C≤8)),        alkenediyl_((C≤8)), or a substituted version of either of these        groups;    -   R₄ and R₅ are each independently absent, hydrogen; or        -   alkyl_((C≤12)), cycloalkyl_((C≤12)),            heterocycloalkyl_((C≤12)), aryl_((C≤12)), aralkyl_((C≤12)),            heteroaryl_((C≤12)), heteroaralkyl_((C≤12)),            -arenediyl_((C≤12))-alkyl_((C≤12)),            -arenediyl_((C≤12))-aryl_((C≤12)),            -arenediyl_((C≤12))-heteroaryl_((C≤12)),            -arenediyl_((C≤12))-heterocycloalkyl_((C≤12)),            -arenediyl_((C≤12))-cycloalkyl_((C≤12)),            -heteroarenediyl_((C≤12))-alkyl_((C≤12)),            -heteroarenediyl_((C≤12))-aryl_((C≤12)),            -heteroarenediyl_((C≤12))-heteroaryl_((C≤12)),            -heteroarenediyl_((C≤12))-hetero-cycloalkyl_((C≤12)),            -heteroarenediyl_((C≤12))-cycloalkyl_((C≤12)),            -heterocyclo-alkanediyl_((C≤12))-aryl_((C≤12)),            -heterocycloalkanediyl_((C≤12))-heteroaryl_((C≤12)), or a            substituted version of any of these groups; or        -   a group of the formula:

-   -   -   wherein l and m are each 0, 1, 2, or 3; and

    -   R₆ is absent, hydrogen; or        -   alkylamino_((C≤12)), dialkylamino_((C≤12)),            cycloalkylamino_((C≤12)), dicycloalkylamino_((C≤12)),            alkyl(cycloalkyl)amino_((C≤12)), arylamino_((C≤12)),            diarylamino_((C≤12)), alkyl_((C≤12)), cycloalkyl_((C≤12)),            -alkanediyl_((C≤12))-cycloalkyl_((C≤12)),            -alkanediyl_((C≤18))-aralkoxy_((C≤18)),            heterocycloalkyl_((C≤12)), aryl_((C≤18)),            -arenediyl_((C≤12))-alkyl_((C≤12)), aralkyl_((C≤18)),            -arenediyl_((C≤18))-heterocycloalkyl_((C≤12)),            heteroaryl_((C≤18)),            -heteroarenediyl_((C≤12))-alkyl_((C≤12)),            heteroaralkyl_((C≤18)), acyl_((C≤12)), alkoxy_((C≤12)), or a            substituted version of any of these groups;            or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is further defined as:

wherein:

-   -   R₄ and R₅ are each independently absent, hydrogen; or        -   alkyl_((C≤12)), cycloalkyl_((C≤12)),            heterocycloalkyl_((C≤12)), aryl_((C≤12)), aralkyl_((C≤12)),            heteroaryl_((C≤12)), heteroaralkyl_((C≤12)),            -arenediyl_((C≤12))-alkyl_((C≤12)),            -arenediyl_((C≤12))-aryl_((C≤12)),            -arenediyl_((C≤12))-heteroaryl_((C≤12)),            -arenediyl_((C≤12))-heterocycloalkyl_((C≤12)),            -arenediyl_((C≤12))-cycloalkyl_((C≤12)),            -heteroarenediyl_((C≤12))-alkyl_((C≤12)),            -heteroarenediyl_((C≤12))-aryl_((C≤12)),            -heteroarenediyl_((C≤12))-heteroaryl_((C≤12)),            -heteroarenediyl_((C≤12))-hetero-cycloalkyl_((C≤12)),            -heteroarenediyl_((C≤12))-cycloalkyl_((C≤12)),            -heterocyclo-alkanediyl_((C≤12))-aryl_((C≤12)),            -heterocycloalkanediyl_((C≤12))-heteroaryl_((C≤12)), or a            substituted version of any of these groups; or        -   a group of the formula:

-   -   -   wherein l and m are each 0, 1, 2, or 3; and

    -   R₆ is absent, hydrogen; or        -   alkylamino_((C≤12)), dialkylamino_((C≤12)),            cycloalkylamino_((C≤12)), dicycloalkylamino_((C≤12)),            alkyl(cycloalkyl)amino_((C≤12)), arylamino_((C≤12)),            diarylamino_((C≤12)), alkyl_((C≤12)), cycloalkyl_((C≤12)),            -alkanediyl_((C≤12))-cycloalkyl_((C≤12)),            -alkanediyl_((C≤18))-aralkoxy_((C≤18)),            heterocycloalkyl_((C≤12)), aryl_((C≤18)),            -arenediyl_((C≤12))-alkyl_((C≤12)), aralkyl_((C≤18)),            -arenediyl_((C≤18))-heterocycloalkyl_((C≤12)),            heteroaryl_((C≤18)),            -heteroarenediyl_((C≤12))-alkyl_((C≤12)),            heteroaralkyl_((C≤18)), acyl_((C≤12)), alkoxy_((C≤12)), or a            substituted version of any of these groups; and

    -   X₁ and X₂ are each independently C or N, provided that X₂ is C        when R₆ is amino, alkylamino_((C≤12)), dialkylamino_((C≤12)),        cycloalkylamino_((C≤12)), dicycloalkylamino_((C≤12)),        alkyl(cycloalkyl)amino_((C≤12)), arylamino_((C≤12)), or        diarylamino_((C≤12));        or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is further defined as:

wherein:

-   -   R₄ and R₅ are each independently absent, hydrogen; or        -   alkyl_((C≤12)), cycloalkyl_((C≤12)),            heterocycloalkyl_((C≤12)), aryl_((C≤12)), aralkyl_((C≤12)),            heteroaryl_((C≤12)), heteroaralkyl_((C≤12)),            -arenediyl_((C≤12))-alkyl_((C≤12)),            -arenediyl_((C≤12))-aryl_((C≤12)),            -arenediyl_((C≤12))-heteroaryl_((C≤12)),            -arenediyl_((C≤12))-heterocycloalkyl_((C≤12)),            -arenediyl_((C≤12))-cycloalkyl_((C≤12)),            -heteroarenediyl_((C≤12))-alkyl_((C≤12)),            -heteroarenediyl_((C≤12))-aryl_((C≤12)),            -heteroarenediyl_((C≤12))-heteroaryl_((C≤12)),            -heteroarenediyl_((C≤12))-hetero-cycloalkyl_((C≤12)),            -heteroarenediyl_((C≤12))-cycloalkyl_((C≤12)),            -heterocyclo-alkanediyl_((C≤12))-aryl_((C≤12)),            -heterocycloalkanediyl_((C≤12))-heteroaryl_((C≤12)), or a            substituted version of any of these groups; or        -   a group of the formula:

-   -   -   wherein l and m are each 0, 1, 2, or 3; and

    -   R₆ is absent, hydrogen; or        -   alkylamino_((C≤12)), dialkylamino_((C≤12)),            cycloalkylamino_((C≤12)), dicycloalkylamino_((C≤12)),            alkyl(cycloalkyl)amino_((C≤12)), arylamino_((C≤12)),            diarylamino_((C≤12)), alkyl_((C≤12)), cycloalkyl_((C≤12)),            -alkanediyl_((C≤12))-cycloalkyl_((C≤12)),            -alkanediyl_((C≤18))-aralkoxy_((C≤18)),            heterocycloalkyl_((C≤12)), aryl_((C≤18)),            -arenediyl_((C≤12))-alkyl_((C≤12)), aralkyl_((C≤18)),            -arenediyl_((C≤18))-heterocycloalkyl_((C≤12)),            heteroaryl_((C≤18)),            -heteroarenediyl_((C≤12))-alkyl_((C≤12)),            heteroaralkyl_((C≤18)), acyl_((C≤12)), alkoxy_((C≤12)), or a            substituted version of any of these groups;            or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is further defined as:

wherein:

-   -   R₄ and R₅ are each independently absent, hydrogen; or        -   alkyl_((C≤12)), cycloalkyl_((C≤12)),            heterocycloalkyl_((C≤12)), aryl_((C≤12)), aralkyl_((C≤12)),            heteroaryl_((C≤12)), heteroaralkyl_((C≤12)),            -arenediyl_((C≤12))-alkyl_((C≤12)),            -arenediyl_((C≤12))-aryl_((C≤12)),            -arenediyl_((C≤12))-heteroaryl_((C≤12)),            -arenediyl_((C≤12))-heterocycloalkyl_((C≤12)),            -arenediyl_((C≤12))-cycloalkyl_((C≤12)),            -heteroarenediyl_((C≤12))-alkyl_((C≤12)),            -heteroarenediyl_((C≤12))-aryl_((C≤12)),            -heteroarenediyl_((C≤12))-heteroaryl_((C≤12)),            -heteroarenediyl_((C≤12))-hetero-cycloalkyl_((C≤12)),            -heteroarenediyl_((C≤12))-cycloalkyl_((C≤12)),            -heterocyclo-alkanediyl_((C≤12))-aryl_((C≤12)),            -heterocycloalkanediyl_((C≤12))-heteroaryl_((C≤12)), or a            substituted version of any of these groups; or        -   a group of the formula:

-   -   -   wherein l and m are each 0, 1, 2, or 3; and

    -   R₆ is absent, hydrogen; or        -   alkylamino_((C≤12)), dialkylamino_((C≤12)),            cycloalkylamino_((C≤12)), dicycloalkylamino_((C≤12)),            alkyl(cycloalkyl)amino_((C≤12)), arylamino_((C≤12)),            diarylamino_((C≤12)), alkyl_((C≤12)), cycloalkyl_((C≤12)),            -alkanediyl_((C≤12))-cycloalkyl_((C≤12)),            -alkanediyl_((C≤18))-aralkoxy_((C≤18)),            heterocycloalkyl_((C≤12)), aryl_((C≤18)),            -arenediyl_((C≤12))-alkyl_((C≤12)), aralkyl_((C≤18)),            -arenediyl_((C≤18))-heterocycloalkyl_((C≤12)),            heteroaryl_((C≤18)),            -heteroarenediyl_((C≤12))-alkyl_((C≤12)),            heteroaralkyl_((C≤18)), acyl_((C≤12)), alkoxy_((C≤12)), or a            substituted version of any of these groups;            or a pharmaceutically acceptable salt thereof.

In some embodiments, X₁ and X₂ are both N. In other embodiments, X₁ andX₂ are not both N. In some embodiments, either X₁ or X₂ is N. In someembodiments, X₁ is N. In some embodiments, X₂ is N. In some embodiments,R₃ is alkyl_((C≤12)) or substituted alkyl_((C≤12)). In furtherembodiments, R₃ is alkyl_((C≤12)), such as methyl. In some embodiments,R₁ is cyano. In other embodiments, R₁ is —C(O)R_(a). In someembodiments, R_(a) is alkoxy_((C≤6)), such as methoxy. In otherembodiments, R_(a) is amino. In some embodiments, R_(2′) is hydrogen. Insome embodiments, R₂ is hydrogen. In some embodiments, R_(2′) and R₂ areboth hydrogen. In other embodiments, R₂ is alkyl_((C≤12)) or substitutedalkyl_((C≤12)). In further embodiments, R₂ is alkyl_((C≤12)), such asmethyl.

In some embodiments, R₄ is absent. In other embodiments, R₄ is hydrogen.In still other embodiments, R₄ is alkyl_((C≤12)) or substitutedalkyl_((C≤12)). In further embodiments, R₄ is substitutedalkyl_((C≤12)), such as R₄ is 2,2,2-trifluoroethyl. In still otherembodiments, R₄ is cycloalkyl_((C≤12)) or substitutedcycloalkyl_((C≤12)). In further embodiments, R₄ is cycloalkyl_((C≤12)),such as cyclohexyl. In yet other embodiments, R₄ isheterocycloalkyl_((C≤12)) or substituted heterocycloalkyl_((C≤12)). Infurther embodiments, R₄ is heterocycloalkyl_((C≤12)), such astetrahydro-2H-pyran-4-yl or 1,1-dioxidotetrahydrothiophen-3-yl. In otherembodiments, R₄ is:

wherein:

l and m are each 0, 1, 2, or 3.

In some embodiments, l is 1 or 2. In some embodiments, m is 1 or 2. Instill other embodiments, R₄ is aryl_((C≤18)), heteroaryl_((C≤18)), or asubstituted version of either of these groups. In further embodiments,R₄ is aryl_((C≤18)) or substituted aryl_((C≤18)). In still furtherembodiments, R₄ is aryl_((C≤18)), such as phenyl, o-tolyl, p-tolyl,[1,1′-biphenyl]-4-yl, 4-isopropylphenyl, naphthalen-1-yl,4′-methyl-[1,1′-biphenyl]-4-yl, or 2′-methyl-[1,1′-biphenyl]-4-yl. Inyet other embodiments, R₄ is substituted aryl_((C≤18)), such as4-(trifluoromethyl)phenyl, 4-cyanophenyl, 2-fluorophenyl,4-fluorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 4-methoxyphenyl,4-(trifluoromethoxy)phenyl, 4-carboxyphenyl,4′-methoxy-[1,1′-biphenyl]-4-yl, 4′-(dimethylamino)[1,1′-biphenyl]-4-yl,2′-fluoro-[1,1′-biphenyl]-4-yl, 3′-fluoro-[1,1′-biphenyl]-4-yl,2′-(hydroxymethyl)[1,1′-biphenyl]-4-yl,3′-(hydroxymethyl)-[1,1′-biphenyl]-4-yl,4′-(hydroxymethyl)-[1,1′-biphenyl]-4-yl, or 5-(3-(hydroxymethyl)phenyl.In other embodiments, R₄ is aralkyl_((C≤18)) or substitutedaralkyl_((C≤18)). In further embodiments, R₄ is aralkyl_((C≤18)), suchas benzyl. In still other embodiments, R₄ is-arenediyl_((C≤12))-heterocycloalkyl_((C≤12)) or substituted-arenediyl_((C≤12))-heterocycloalkyl_((C≤12)). In further embodiments,R₄ is -arenediyl_((C≤12))-heterocycloalkyl_((C≤12)), such as4-morpholinophenyl. In other embodiments, R₄ is heteroaryl_((C≤18)) orsubstituted heteroaryl_((C≤18)). In further embodiments, R₄ isheteroaryl_((C≤18)), such as pyridin-4-yl, quinolin-4-yl,5-methylpyrindin-2-yl, 6-methylpyrindin-3-yl, (pyridin-3-yl)phenyl,(pyridin-4-yl)phenyl, 4-(3,5-dimethylisoxazol-4-yl)phenyl,4-(pyrimidin-4-yl)phenyl, 4-(pyrimidin-5-yl)phenyl,4-(pyridin-3-yl)phenyl, 4-(pyridin-4-yl)phenyl, 5-phenylpyridin-2-yl,[3,3′-bipyridin]-6-yl, 5-cyclopropylpyridin-2-yl, 6-phenylpyridin-3-yl,4-(6-methylpyridazin-4-yl)phenyl, 5-methyl-1,2,4-oxadiazol-3-yl,3-methyl-1,2,4-oxadiazol-5-yl, 4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl,1-phenylpiperidin-4-yl, 4-phenyloxazol-2-yl,4-(6-methylpyridazin-4-yl)phenyl,4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl,4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl, 4-(1,2,4-oxadiazol-3-yl)phenyl,4-(pyridazin-3-yl)phenyl, 4-(5-methylpyridazin-3-yl)phenyl,1-methyl-1H-benzo[d]imidazol-2-yl, or benzo[d]thiazol-2-yl. In stillother embodiments, R₄ is substituted heteroaryl_((C≤18)), such as2-fluoro-4-(pyridin-3-yl)phenyl, 5-(trifluoromethyl)pyridin-2-yl,5-(3-fluorophenyl)pyridin-2-yl, 5-(4-fluorophenyl)pyridin-2-yl,4-(2-(hydroxymethyl)pyridine-4-yl)phenyl,4-(2-(fluoromethyl)pyridine-4-yl)phenyl,5-(trifluoromethyl)benzo[d]oxazol-2-yl, 6-chlorobenzo[d]thiazol-2-yl, or4-(5-fluoropyridin-3-yl)phenyl.

In some embodiments, R₅ is absent. In other embodiments, R₅ is hydrogen.In still other embodiments, R₅ is alkyl_((C≤12)) or substitutedalkyl_((C≤12)). In further embodiments, R₅ is alkyl_((C≤12)), such asmethyl. In yet other embodiments, R₅ is cycloalkyl_((C≤12)) orsubstituted cycloalkyl_((C≤12)). In further embodiments, R₅ iscycloalkyl_((C≤12)), such as cyclohexyl. In other embodiments, R₅ isheterocycloalkyl_((C≤12)) or substituted heterocycloalkyl_((C≤12)). Infurther embodiments, R₅ is heterocycloalkyl_((C≤12)), such astetrahydro-2H-pyran-4-yl. In still other embodiments, R₅ isaryl_((C≤18)) or substituted aryl_((C≤18)). In further embodiments, R₅is aryl_((C≤18)), such as phenyl, o-tolyl, p-tolyl,[1,1′-biphenyl]-4-yl, 4-isopropylphenyl, naphthalen-1-yl,[1,1′-biphenyl]-3-yl, or 3-isopropylphenyl. In yet other embodiments, R₅is substituted aryl_((C≤18)), such as 4-chlorophenyl,3,4-dichlorophenyl, 4-methoxyphenyl, 4-(trifluoromethoxy)phenyl,3-bromophenyl, 3-chlorophenyl, 4-(dimethylamino)phenyl. In otherembodiments, R₅ is aralkyl_((C≤18)) or substituted aralkyl_((C≤18)). Infurther embodiments, R₅ is aralkyl_((C≤18)), such as R₅ is benzyl. Instill other embodiments, R₅ is-arenediyl_((C≤12))-heterocycloalkyl_((C≤12)) or substituted-arenediyl_((C≤12))-heterocycloalkyl_((C≤12)). In further embodiments,R₅ is -arenediyl_((C≤12))-heterocycloalkyl_((C≤12)), such as3-morpholinophenyl. In yet other embodiments, R₅ is heteroaryl_((C≤18))or substituted heteroaryl_((C≤18)). In further embodiments,heteroaryl_((C≤18)), such as pyridin-4-yl, quinolin-4-yl, quinolin-3-yl,quinolin-5-yl, 3-(pyridin-4-yl)phenyl, 3-(pyrimidin-5-yl)phenyl,2-isopropylpyrimidin-5-yl, 6-cyclopropylpyridin-3-yl,3-(1-methyl-1H-pyrazol-4-yl)phenyl, 1-methyl-1H-pyrazol-4-yl,3-(3,5-dimethylisoxazol-4-yl)phenyl, 3-(1-methyl-1H-pyrazol-5-yl)phenyl,or 2-cyclopropylpyridin-4-yl. In other embodiments, R₅ is substitutedheteroaryl_((C≤18)), such as 2-(trifluoromethyl)pyridin-4-yl or3-(5-fluoropyridin-3-yl)phenyl. In still other embodiments, R₅ is-heteroarenediyl_((C≤12))-heterocycloalkyl_((C≤12)) or substituted-heteroarenediyl_((C≤12))-heterocycloalkyl_((C≤12)). In furtherembodiments, R₅ is -heteroarenediyl_((C≤12))-heterocycloalkyl_((C≤12)),such as 2-morpholinopyridin-4-yl.

In some embodiments, R₆ is hydrogen. In other embodiments, R₆ isaryl_((C≤18)), heteroaryl_((C≤18)), or a substituted version of eitherof these groups. In still other embodiments, R₆ is amino. In yet otherembodiments, R₆ is alkylamino_((C≤12)) or substitutedalkylamino_((C≤12)). In further embodiments, R₆ is alkylamino_((C≤12)),such as methylamino. In other embodiments, R₆ iscycloalkylamino_((C≤12)) or substituted cycloalkylamino_((C≤12)). Infurther embodiments, R₆ is cycloalkylamino_((C≤12)), such ascyclobutylamino. In still other embodiments, R₆ isalkyl(cycloalkyl)amino_((C≤12)) or substitutedalkyl(cycloalkyl)amino_((C≤12)). In further embodiments, R₆ isalkyl(cycloalkyl)amino_((C≤12)), such as methyl(cyclobutyl)amino. In yetother embodiments, R₆ is arylamino_((C≤12)) or substitutedarylamino_((C≤12)). In further embodiments, R₆ is arylamino_((C≤12)),such as phenylamino. In other embodiments, R₆ is alkyl_((C≤12)) orsubstituted alkyl_((C≤12)). In further embodiments, R₆ isalkyl_((C≤12)), such as methyl. In still other embodiments, R₆ issubstituted alkyl_((C≤12)), such as 2-hydroxyethyl or 2-methoxyethyl. Inyet other embodiments, R₆ is acyl_((C≤6)) or substituted acyl_((C≤6)).In further embodiments, R₆ is acyl_((C≤6)), such as C(O)CH₃. In otherembodiments, R₆ is cycloalkyl_((C≤12)) or substitutedcycloalkyl_((C≤12)). In further embodiments, R₆ is cycloalkyl_((C≤12)),such as cyclopropyl or cyclohexyl. In still other embodiments, R₆ is-alkanediyl_((C≤18))-cycloalkyl_((C≤18)) or substituted-alkanediyl_((C≤18))-cycloalkyl_((C≤18)). In further embodiments, R₆ is-alkanediyl_((C≤18))-cycloalkyl_((C≤18)), such as cyclobutylmethyl. Inyet other embodiments, R₆ is aryl_((C≤18)) or substituted aryl_((C≤18)).In further embodiments, R₆ is aryl_((C≤18)), such as phenyl, o-tolyl,p-tolyl, or 3-isopropylphenyl. In other embodiments, R₆ is substitutedaryl_((C≤18)), such as 2-fluorophenyl, 4-fluorophenyl,4-(hydroxymethyl)phenyl, 3-fluorophenyl, or 4-(fluoromethyl)phenyl. Instill other embodiments, R₆ is aralkyl_((C≤18)) or substitutedaralkyl_((C≤18)). In further embodiments, R₆ is aralkyl_((C≤18)), suchas benzyl. In yet other embodiments, R₆ is substituted aralkyl_((C≤18)),such as 2-fluorobenzyl, 4-fluorobenzyl, or 4-chlorobenzyl. In otherembodiments, R₆ is -arenediyl_((C≤18))-heterocycloalkyl_((C≤12)) orsubstituted -arenediyl_((C≤18))-heterocycloalkyl_((C≤12)). In furtherembodiments, R₆ is -arenediyl_((C≤18))-heterocycloalkyl_((C≤12)), suchas 4-morpholinophenyl. In still other embodiments, R₆ isheteroaryl_((C≤18)) or substituted heteroaryl_((C≤18)). In furtherembodiments, R₆ is heteroaryl_((C≤18)), such as pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, 2-methyl-2H-tetrazol-5-yl,1-methyl-1H-pyrazol-4-yl, pyrimidin-4-yl, pyrimidin-5-yl,3-methyl-1,2,4-oxadiazol-5-yl)phenyl, pyridin-2-ylmethyl,3-methyl-1,2,4-oxadiazol-5-yl, or 5-methyl-1,2,4-oxadiazol-3-yl. Instill other embodiments, R₆ is heteroaralkyl_((C≤18)) orheteroaralkyl_((C≤18)). In further embodiments, R₆ isheteroaralkyl_((C≤18)), such as 2-pyridinylmethyl or 4-pyridinylmethyl.In yet other embodiments, R₆ is -alkanediyl_((C≤18))-aralkoxy_((C≤18))or substituted -alkanediyl_((C≤18))-aralkoxy_((C≤18)). In furtherembodiments, R₆ is -alkanediyl_((C≤18))-aralkoxy_((C≤18)), such as2-(benzyloxy)ethyl.

In some embodiments, the compound is further defined as:

or a pharmaceutically acceptable salt of any of the above formulas.

In some embodiments, the compound is further defined as:

or a pharmaceutically acceptable salt of any of the above formulas.

In some embodiments, the therapeutically effective amount is a dailydose is 0.01-100 mg of inverse agonist per kg of body weight. In someembodiments, the daily dose is 0.05-30 mg of inverse agonist per kg ofbody weight. In some embodiments, the daily dose is 0.1-10 mg of inverseagonist per kg of body weight. In some embodiments, the daily dose is0.1-5 mg of inverse agonist per kg of body weight. In some embodiments,the daily dose is 0.1-2.5 mg of inverse agonist per kg of body weight.

In some embodiments, the inverse agonist is administered as a singledose to the patient per day. In other embodiments, the inverse agonistis administered as two or more doses to the patient per day. In someembodiments, the inverse agonist is administered orally, intraarteriallyor intravenously. In some embodiments, the inverse agonist is formulatedas a hard or soft capsule or a tablet.

In still another aspect, the present disclosure provides compounds ofthe formula:

or a pharmaceutically acceptable salt thereof.

In yet another aspect, the present disclosure provides pharmaceuticalcompositions comprising a compound of the present disclosure and anexcipient.

In some embodiments, the pharmaceutical composition is formulated foradministration: orally, intraadiposally, intraarterially,intraarticularly, intracranially, intradermally, intralesionally,intramuscularly, intranasally, intraocularly, intrapericardially,intraperitoneally, intrapleurally, intraprostatically, intrarectally,intrathecally, intratracheally, intratumorally, intraumbilically,intravaginally, intravenously, intravesicularlly, intravitreally,liposomally, locally, mucosally, parenterally, rectally,subconjunctival, subcutaneously, sublingually, topically, transbuccally,transdermally, vaginally, in crèmes, in lipid compositions, via acatheter, via a lavage, via continuous infusion, via infusion, viainhalation, via injection, via local delivery, or via localizedperfusion. In some embodiments, the pharmaceutical composition isformulated for oral administration. In other embodiments, thepharmaceutical composition is formulated for administration viainjection such as for intraarterial administration, intramuscularadministration, intraperitoneal administration, or intravenousadministration. In other embodiments, the pharmaceutical composition isformulated for administration topically such as for topicaladministration to the skin or to the eye. In some embodiments, thepharmaceutical composition is formulated as a unit dose.

Other objects, features and advantages of the present disclosure willbecome apparent from the following detailed description. It should beunderstood, however, that the detailed description and the specificexamples, while indicating specific embodiments of the invention, aregiven by way of illustration only, since various changes andmodifications within the spirit and scope of the invention will becomeapparent to those skilled in the art from this detailed description.Note that simply because a particular compound is ascribed to oneparticular generic formula doesn't mean that it cannot also belong toanother generic formula.

BRIEF DESCRIPTION OF THE DRAWINGS

The following drawings form part of the present specification and areincluded to further demonstrate certain aspects of the presentinvention. The invention may be better understood by reference to one ormore of these drawings in combination with the detailed description ofspecific embodiments presented herein.

FIGS. 1A-1B show the effect of compound 14 on RORα, RORβ, and RORγtactivity.

FIGS. 2A-2D show the effect of compound 14 on Th17 cell differentiation(A) and suppression of TH17 signature genes (B-D).

FIGS. 3A-3B show activity of compound 14 in the mCIA model dosed orallyat 3 mg/kg.

DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

Disclosed herein are methods, compounds, and compositions that may beused to inhibit or modulate the activity of the RORγ nuclear receptorand/or IL-17 by covalent modification of the allosteric binding site.These methods are thus useful in the treatment of a wide variety ofdifferent indications such as autoimmune disease, metabolic diseases,cancer, and infections. These methods may be used to modulate theexpression of one or more downstream compound such as interleukin-17(IL-17) through covalent modification of the RORγ nuclear receptor.

I. COMPOUNDS AND SYNTHETIC METHODS

The compounds of the present invention and the compounds for use withthe present invention (also referred to as “compounds of the presentdisclosure”) are shown, for example, above, in the summary of theinvention section, and in the claims below. They may be made using thesynthetic methods described in PCT/US2017/000094 (WO 2018/111315) andPCT/US2019/037543, the entire contents of which are hereby incorporatedby reference. These methods can be further modified and optimized usingthe principles and techniques of organic chemistry as applied by aperson skilled in the art. Such principles and techniques are taught,for example, in Smith, March's Advanced Organic Chemistry: Reactions,Mechanisms, and Structure, (2013), which is incorporated by referenceherein. In addition, the synthetic methods may be further modified andoptimized for preparative, pilot- or large-scale production, eitherbatch or continuous, using the principles and techniques of processchemistry as applied by a person skilled in the art. Such principles andtechniques are taught, for example, in Anderson, Practical ProcessResearch & Development—A Guide for Organic Chemists (2012), which isincorporated by reference herein.

All the compounds of the present invention may in some embodiments beused for the prevention and treatment of one or more diseases ordisorders discussed herein or otherwise. In some embodiments, one ormore of the compounds characterized or exemplified herein as anintermediate, a metabolite, and/or prodrug, may nevertheless also beuseful for the prevention and treatment of one or more diseases ordisorders. As such unless explicitly stated to the contrary, all thecompounds of the present invention are deemed “active compounds” and“therapeutic compounds” that are contemplated for use as activepharmaceutical ingredients (APIs). Actual suitability for human orveterinary use is typically determined using a combination of clinicaltrial protocols and regulatory procedures, such as those administered bythe Food and Drug Administration (FDA). In the United States, the FDA isresponsible for protecting the public health by assuring the safety,effectiveness, quality, and security of human and veterinary drugs,vaccines and other biological products, and medical devices.

In some embodiments, the compounds of the present invention have theadvantage that they may be more efficacious than, be less toxic than, belonger acting than, be more potent than, produce fewer side effectsthan, be more easily absorbed than, more metabolically stable than, morelipophilic than, more hydrophilic than, and/or have a betterpharmacokinetic profile (e.g., higher oral bioavailability and/or lowerclearance) than, and/or have other useful pharmacological, physical, orchemical properties over, compounds known in the prior art, whether foruse in the indications stated herein or otherwise.

Compounds of the present invention may contain one or moreasymmetrically-substituted carbon or nitrogen atom and may be isolatedin optically active or racemic form. Thus, all chiral, diastereomeric,racemic form, epimeric form, and all geometric isomeric forms of achemical formula are intended, unless the specific stereochemistry orisomeric form is specifically indicated. Compounds may occur asracemates and racemic mixtures, single enantiomers, diastereomericmixtures and individual diastereomers. In some embodiments, a singlediastereomer is obtained. The chiral centers of the compounds of thepresent invention can have the S or the R configuration. In someembodiments, the present compounds may contain two or more atoms whichhave a defined stereochemical orientation.

Chemical formulas used to represent compounds of the present inventionwill typically only show one of possibly several different tautomers.For example, many types of ketone groups are known to exist inequilibrium with corresponding enol groups. Similarly, many types ofimine groups exist in equilibrium with enamine groups. Regardless ofwhich tautomer is depicted for a given compound, and regardless of whichone is most prevalent, all tautomers of a given chemical formula areintended.

In addition, atoms making up the compounds of the present invention areintended to include all isotopic forms of such atoms. Isotopes, as usedherein, include those atoms having the same atomic number but differentmass numbers. By way of general example and without limitation, isotopesof hydrogen include tritium and deuterium, and isotopes of carboninclude ¹³C and ¹⁴C.

In some embodiments, compounds of the present invention function asprodrugs or can be derivatized to function as prodrugs. Since prodrugsare known to enhance numerous desirable qualities of pharmaceuticals(e.g., solubility, bioavailability, manufacturing, etc.), the compoundsemployed in some methods of the invention may, if desired, be deliveredin prodrug form. Thus, the invention contemplates prodrugs of compoundsof the present invention as well as methods of delivering prodrugs.Prodrugs of the compounds employed in the invention may be prepared bymodifying functional groups present in the compound in such a way thatthe modifications are cleaved, either in routine manipulation or invivo, to the parent compound. Accordingly, prodrugs include, forexample, compounds described herein in which a hydroxy, amino, orcarboxy group is bonded to any group that, when the prodrug isadministered to a patient, cleaves to form a hydroxy, amino, orcarboxylic acid, respectively.

In some embodiments, compounds of the present invention exist in salt ornon-salt form. With regard to the salt form(s), in some embodiments theparticular anion or cation forming a part of any salt form of a compoundprovided herein is not critical, so long as the salt, as a whole, ispharmacologically acceptable. Additional examples of pharmaceuticallyacceptable salts and their methods of preparation and use are presentedin Handbook of Pharmaceutical Salts: Properties, and Use (2002), whichis incorporated herein by reference.

It will be appreciated that many organic compounds can form complexeswith solvents in which they are reacted or from which they areprecipitated or crystallized. These complexes are known as “solvates.”Where the solvent is water, the complex is known as a “hydrate.” It willalso be appreciated that many organic compounds can exist in more thanone solid form, including crystalline and amorphous forms. All solidforms of the compounds provided herein, including any solvates thereofare within the scope of the present invention.

II. RORγ AND CYTOKINE IL-17

Without being bound by theory, the presence of a Michael acceptor (MA)in the A ring is important in methods of modulating the activity ofRORγ/RORγt described herein. In particular, the presence of anelectron-withdrawing group at C2 shows strong activity, with a CN groupat C2 showing stronger activity. This relationship suggests that acysteine dependent covalent drug:protein interaction is involved in theactivity of these inhibitors and of related compounds. This mechanism ofaction (MOA) has been explored successfully with other protein classes,most notably with kinases, nonetheless it is rare in the nuclear hormonereceptor field, and unreported in the ROR family. The chemical biologyliterature of NHR's provides few insights on how to triage the eightcysteines on RORγ for their proclivity towards covalent drug:proteininteraction. PPARγ is the lone exception, where it has been noted thatseveral endogenous fatty acid metabolite ligands, e.g. PGJ₂, bind in theorthosteric site through covalent interaction with cysteine 285 on helixH3 and thusly regulate the transcriptional activity. Interestingly,cysteine 320 on alpha helix H3 of RORγt is in the same location ascysteine 285 on PPARγ. Based on this evidence suggesting that cysteine320 of RORγ (see SEQ ID NO: 1; and which is equivalent to cysteine 299in RORγt (see SEQ ID NO: 2)) could be the companion residue of interest,site directed mutation of cysteine 320 to alanine and serine was used toobtain functional proteins that could be used to test this hypothesis.The activities of compounds 14 and 21 were found to be unaffected byboth mutations in the full-length RORγt RORE-luciferase reporter assayin Jurkat cells, i.e., their activity was maintained in the presence ofthese mutations. These observations were supported by competitivebinding studies monitored by mass spectrometry that demonstrated that 14and 21 did not compete with cholesterol sulfate, a known orthostericligand for RORγ/RORγt. Reporter gene constructs wherein each of theremaining seven cysteine residues in the LBD were selectively mutated toa different amino acid residue were prepared. When compounds 14 and 21were assayed against these constructs only the cysteine 476 in RORγ(cysteine 455 in RORγt) mutations led to a reduction in RORγtRORE-luciferase reporter expression in Jurkat cells versus the parentconstruct, demonstrating that this cysteine was the singular residueinvolved in covalent interactions with the Michael acceptor moiety.

-RORγ Protein Sequence: SEQ ID NO: 1 MDRAPQRQHR ASRELLAAKK THTSQIEVIPCKICGDKSSG IHYGVITCEG CKGFFRRSQR CNAAYSCTRQ QNCPIDRTSR NRCQHCRLQKCLALGMSRDA VKFGRMSKKQ RDSLHAEVQK QLQQRQQQQQ EPVVKTPPAG AQGADTLTYTLGLPDGQLPL GSSPDLPEAS ACPPGLLKAS GSGPSYSNNL AKAGLNGASC HLEYSPERGKAEGRESFYST GSQLTPDRCG LRFEEHRHPG LGELGQGPDS YGSPSFRSTP EAPYASLTEIEHLVQSVCKS YRETCQLRLE DLLRQRSNIF SREEVTGYQR KSMWEMWERC AHHLTEAIQYVVEFAKRLSG FMELCQNDQI VLLKAGAMEV VLVRMCRAYN ADNRTVFFEG KYGGMELFRALGCSELISSI FDFSHSLSAL HFSEDEIALY TALVLINAHR PGLQEKRKVE QLQYNLELAFHHHLCKTHRQ SILAKLPPKG KLRSLCSQHV ERLQIFQHLH PIVVQAAFPP LYKELFSTETESPVGLSK -RORγt Protein Sequence: SEQ ID NO: 2 MRTQIEVIPC KICGDKSSGIHYGVITCEGC KGFFRRSQRC NAAYSCTRQQ NCPIDRTSRN RCQHCRLQKC LALGMSRDAVKFGRMSKKQR DSLHAEVQKQ LQQRQQQQQE PVVKTPPAGA QGADTLTYTL GLPDGQLPLGSSPDLPEASA CPPGLLKASG SGPSYSNNLA KAGLNGASCH LEYSPERGKA EGRESFYSTGSQLTPDRCGL RFEEHRHPGL GELGQGPDSY GSPSFRSTPE APYASLTEIE HLVQSVCKSYRETCQLRLED LLRQRSNIFS REEVTGYQRK SMWEMWERCA HHLTEAIQYV VEFAKRLSGFMELCQNDQIV LLKAGAMEVV LVRMCRAYNA DNRTVFFEGK YGGMELFRAL GCSELISSIFDFSHSLSALH FSEDEIALYT ALVLINAHRP GLQEKRKVEQ LQYNLELAFH HHLCKTHRQSILAKLPPKGK LRSLCSQHVE RLQIFQHLHP IVVQAAFPPL YKELFSTETE SPVGLSK

B. Cytokine IL-17

Various reports have implicated the inflammatory cytokine IL-17 in thepathogenesis of many autoimmune diseases, including rheumatoidarthritis, psoriasis and psoriatic arthritis, inflammatory boweldiseases (including but not limited to Crohn's disease), multiplesclerosis, autoimmune nephritis, autoimmune uveitis, Type 1 diabetes,and ankylosing spondylitis. In some embodiments, the compounds providedherein may be administered to a patient in order to treat or prevent oneor more of these diseases or disorders. A type of T lymphocyte known asa Th17 cell is a primary source of IL-17. There are multiple members ofthe IL-17 family. The first identified member, IL-17A, is commonlyreferred to as IL-17. IL-17 is composed of two monomers linked bydisulfide bonds to form a homodimer (Miossec and Kolls, 2012). Asidefrom IL-17A, the other principal family member is IL-17F. Some evidencesuggests that IL-17F and IL-17A, though they have many effects incommon, may have different effects in certain settings such as lunginflammation. The IL-17 cytokines bind to IL-17 receptors (IL-17R)located in the membrane of select cell types. Although there aremultiple subtypes of the IL-17 receptor, the IL-17RA/IL-17RC complex isrequired for the activity of IL-17A and IL-17F. IL-17RA has the unusualproperty of signaling through a pathway that involves an adaptor protein(ACT1) rather than the Janus kinase/signal transducer and activator oftranscription (JAK/STAT) pathway employed by most interleukin receptors.Binding of IL-17A to IL-17RA activates the pro-inflammatory nuclearfactor-kappa B (NF-κB) pathway and pro-inflammatory elements of themitogen-activated protein kinase (MAPK) pathway such as JUN N-terminalkinase (JNK), p38 and extracellular signal-related kinase (ERK). IL-17activity stimulates secretion of IL-6 and IL-8 from mesenchymal cellsand leads to fever along with the accumulation of neutrophils in bloodand tissue. In some embodiments, the compounds provided herein may beused to inhibit the secretion of IL-6 and IL-8 from mesenchymal cells.In some embodiments, the compounds provided herein may be administeredto a patient in order to prevent or inhibit fever in a patient. In someembodiments, the compounds provided herein may be administered to apatient in order to prevent the accumulation of neutrophils in the bloodor tissue of the patient.

Aside from its contribution to acute inflammation, IL-17 alsocontributes to chronic inflammation (Miossec and Kolls, 2012). In someembodiments, the compounds provided herein may be administered to apatient in order to prevent or treat chronic inflammation. IL-17stimulates the production of matrix metalloproteinases (MMPs), whichamong other effects can degrade cartilage in joints. In someembodiments, the compounds provided herein may be administered to apatient in order to prevent or treat degradation of the patient'scartilage. IL-17 also increases the expression of receptor activator ofNF-κB ligand (RANKL) in osteoblasts, leading to differentiation andactivation of osteoclasts and bone degradation. In some embodiments, thecompounds provided herein may be administered to a patient in order toprevent or treat degradation of the patient's bone. Depending on thetarget cell that is exposed to it, IL-17 may stimulate the production ofIL-6, IL-8, IL-1, tumor necrosis factor (TNF), MMPs, nitric oxide, orseveral other proteins that are implicated in inflammatory conditions(e.g., tissue factor, CCL20, G-CSF and GM-CSF). In some embodiments, thecompounds provided herein may be administered to a patient in order toinhibit the production of IL-6, IL-8, IL-1, tumor necrosis factor (TNF),MMPs, nitric oxide, or several other proteins that are implicated ininflammatory conditions (e.g., tissue factor, CCL20, G-CSF and GM-CSF).

Although IL-17 plays a role in the immune response to invadingpathogens, excessive IL-17 activity has been implicated in pathologiesassociated with an excessive immune response to an infection. In someembodiments, the compounds provided herein may be administered to apatient in order to prevent or treat excessive immune response to aninfection. For example, IL-17 has been implicated in the severeneuroinflammation associated with Toxoplasma gondii infection andincreased severity of lesions associated with Leishmania infection. Insome embodiments, the compounds provided herein may be administered to apatient in order to treat or prevent neuroinflammation, for example,neuroinflammation associated with Toxoplasma gondii infection. In someembodiments, the compounds provided herein may be administered to apatient in order to treat or prevent lesions associated with Leishmaniainfection. In these and other cases, IL-17 appears to play a role inperpetuating the infection, promoting an excessive inflammatoryresponse, and inhibiting clearance of the infectious agent (Waite andSkokos, 2012). In some embodiments, the compounds provided herein may beadministered to a patient in order to prevent an excessive inflammatoryresponse and/or promote the clearance of an infectious agent.

Drugs targeting IL-17 have entered clinical trials for a wide variety ofinflammatory conditions, including psoriasis, rheumatoid arthritis,ankylosing spondylitis, uveitis, Behcet's disease, psoriatic arthritis,Crohn's disease, polymyalgia rheumatica, dry eye syndrome, multiplesclerosis, graft-versus-host disease, and asthma. In some embodiments,the compounds provided herein may be administered to a patient in orderto treat or prevent one or more of these diseases or disorders.Preclinical evidence also implicates IL-17 in the pathology of type 1diabetes, and Th17 cells are elevated in patients with adult onsetStill's disorder, another autoimmune disease. In some embodiments, thecompounds provided herein may be administered to a patient in order totreat type 1 diabetes. In some embodiments, the compounds providedherein may be administered to a patient in order to treat or preventadult onset Still's disorder. Activity of Th17 cells has been implicatedin the development of graft-versus-host disease following allogeneicstem cell (e.g., bone marrow) transplantation (Fujiwara, et al., 2014).In some embodiments, the compounds provided herein may be administeredto a patient in order to treat or prevent graft-versus-host disease, forexample, following allogeneic stem cell (e.g., bone marrow)transplantation. Given the large body of evidence to date, it is likelythat therapies reducing the expression of IL-17 or otherwise reducingits levels in circulation or target tissues (e.g., anti-IL17 monoclonalantibodies) could have broad applications in the treatment of autoimmunediseases and other inflammatory conditions. In some embodiments, thecompounds provided herein may be administered to a patient in order toreduce the expression of IL-17 or its levels in circulation or targettissues (e.g., anti-IL17 monoclonal antibodies). In some embodiments,the compounds provided herein may be administered to a patient in orderto treat autoimmune diseases or other inflammatory conditions.

Overproduction of IL-17 or elevated numbers of Th17 cells have beenreported in patient studies or animal models of a large number ofconditions, including autoimmune diseases, neurological disorders,cardiovascular diseases, cancer, psychiatric and neuropsychiatricdisorders, acute and chronic inflammatory conditions, chronic painsyndromes, organ rejection or graft-versus-host disease, or asthma andother allergic conditions. In some embodiments, the compounds providedherein may be administered to a patient in order to treat or prevent oneor more of these diseases or disorders.

Both the differentiation of Th17 cells and their production of IL-17 areregulated to a significant degree by the retinoid orphan receptor RORγt,a member of the nuclear hormone receptor family. Expression of RORγt iscommon to all types of Th17 cells. RORγ also regulates the production ofIL-17 in other cell types, including γδ T cells, innate lymphoid cells,and lymphoid tissue inducer cells (Bronner et al., 2016). Inhibition ofRORγt activity results in reduced expression of IL-17. In someembodiments, the compounds provided herein my be administered to apatient in order to inhibit RORγt activity.

Compounds and compositions provided and disclosed herein may be used tosuppress IL-17 production in cultures of human T cells that are exposedto a mixture of cytokines known to induce differentiation into Th17cells. In some embodiments, the ability to act as inverse agonists ofRORγt is also demonstrated. Without wishing to be bound by any theory,it is believed that, for example, RORγt-independent mechanisms appear tocontribute to the suppression of IL-17 production. Thus, the compoundsand compositions provided herein may be used for inhibitingdifferentiation of T cells into Th17 cells, as well as inhibitingproduction of IL-17 by mature Th17 cells. In some of these embodiments,the net result is a reduction in IL-17 levels. In some embodiments, thecompounds provided herein may be administered to a patient in order tosuppress IL-17 production in one or more of the patient's tissues ororgans.

III. PHARMACEUTICAL FORMULATIONS AND ROUTES OF ADMINISTRATION

In another aspect, for administration to a patient in need of suchtreatment, pharmaceutical formulations (also referred to as apharmaceutical preparations, pharmaceutical compositions, pharmaceuticalproducts, medicinal products, medicines, medications, or medicaments)comprise a therapeutically effective amount of a compound disclosedherein formulated with one or more excipients and/or drug carriersappropriate to the indicated route of administration. In someembodiments, the compounds disclosed herein are formulated in a manneramenable for the treatment of human and/or veterinary patients. In someembodiments, formulation comprises admixing or combining one or more ofthe compounds disclosed herein with one or more of the followingexcipients: lactose, sucrose, starch powder, cellulose esters ofalkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesiumstearate, magnesium oxide, sodium and calcium salts of phosphoric andsulfuric acids, gelatin, acacia, sodium alginate, polyvinylpyrrolidone,and/or polyvinyl alcohol. In some embodiments, e.g., for oraladministration, the pharmaceutical formulation may be tableted orencapsulated. In some embodiments, the compounds may be dissolved orslurried in water, polyethylene glycol, propylene glycol, ethanol, cornoil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodiumchloride, and/or various buffers. In some embodiments, thepharmaceutical formulations may be subjected to pharmaceuticaloperations, such as sterilization, and/or may contain drug carriersand/or excipients such as preservatives, stabilizers, wetting agents,emulsifiers, encapsulating agents such as lipids, dendrimers, polymers,proteins such as albumin, nucleic acids, and buffers.

Pharmaceutical formulations may be administered by a variety of methods,e.g., orally or by injection (e.g. subcutaneous, intravenous, andintraperitoneal). Depending on the route of administration, thecompounds disclosed herein may be coated in a material to protect thecompound from the action of acids and other natural conditions which mayinactivate the compound. To administer the active compound by other thanparenteral administration, it may be necessary to coat the compoundwith, or co-administer the compound with, a material to prevent itsinactivation. In some embodiments, the active compound may beadministered to a patient in an appropriate carrier, for example,liposomes, or a diluent. Pharmaceutically acceptable diluents includesaline and aqueous buffer solutions. Liposomes includewater-in-oil-in-water CGF emulsions as well as conventional liposomes.

The compounds disclosed herein may also be administered parenterally,intraperitoneally, intraspinally, or intracerebrally. Dispersions can beprepared in glycerol, liquid polyethylene glycols, and mixtures thereofand in oils. Under ordinary conditions of storage and use, thesepreparations may contain a preservative to prevent the growth ofmicroorganisms.

Pharmaceutical compositions suitable for injectable use include sterileaqueous solutions (where water soluble) or dispersions and sterilepowders for the extemporaneous preparation of sterile injectablesolutions or dispersion. The carrier can be a solvent or dispersionmedium containing, for example, water, ethanol, polyol (such as,glycerol, propylene glycol, and liquid polyethylene glycol, and thelike), suitable mixtures thereof, and vegetable oils. The properfluidity can be maintained, for example, by the use of a coating such aslecithin, by the maintenance of the required particle size in the caseof dispersion and by the use of surfactants. Prevention of the action ofmicroorganisms can be achieved by various antibacterial and antifungalagents, for example, parabens, chlorobutanol, phenol, ascorbic acid,thimerosal, and the like. In many cases, it will be preferable toinclude isotonic agents, for example, sugars, sodium chloride, orpolyalcohols such as mannitol and sorbitol, in the composition.Prolonged absorption of the injectable compositions can be brought aboutby including in the composition an agent which delays absorption, forexample, aluminum monostearate or gelatin.

The compounds disclosed herein can be administered orally, for example,with an inert diluent or an assailable edible carrier. The compounds andother ingredients may also be enclosed in a hard or soft-shell gelatincapsule, compressed into tablets, or incorporated directly into thepatient's diet. For oral therapeutic administration, the compoundsdisclosed herein may be incorporated with excipients and used in theform of ingestible tablets, buccal tablets, troches, capsules, elixirs,suspensions, syrups, wafers, and the like. The percentage of thetherapeutic compound in the compositions and preparations may, ofcourse, be varied. The amount of the therapeutic compound in suchpharmaceutical formulations is such that a suitable dosage will beobtained.

The therapeutic compound may also be administered topically to the skin,eye, ear, or mucosal membranes. Administration of the therapeuticcompound topically may include formulations of the compounds as atopical solution, lotion, cream, ointment, gel, foam, transdermal patch,or tincture. When the therapeutic compound is formulated for topicaladministration, the compound may be combined with one or more agentsthat increase the permeability of the compound through the tissue towhich it is administered. In other embodiments, it is contemplated thatthe topical administration is administered to the eye. Suchadministration may be applied to the surface of the cornea, conjunctiva,or sclera. Without wishing to be bound by any theory, it is believedthat administration to the surface of the eye allows the therapeuticcompound to reach the posterior portion of the eye. Ophthalmic topicaladministration can be formulated as a solution, suspension, ointment,gel, or emulsion. Finally, topical administration may also includeadministration to the mucosa membranes such as the inside of the mouth.Such administration can be directly to a particular location within themucosal membrane such as a tooth, a sore, or an ulcer. Alternatively, iflocal delivery to the lungs is desired the therapeutic compound may beadministered by inhalation in a dry-powder or aerosol formulation.

In some embodiments, it may be advantageous to formulate parenteralcompositions in dosage unit form for ease of administration anduniformity of dosage. Dosage unit form as used herein refers tophysically discrete units suited as unitary dosages for the patients tobe treated; each unit containing a predetermined quantity of therapeuticcompound calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical carrier. In someembodiments, the specification for the dosage unit forms of theinvention are dictated by and directly dependent on (a) the uniquecharacteristics of the therapeutic compound and the particulartherapeutic effect to be achieved, and (b) the limitations inherent inthe art of compounding such a therapeutic compound for the treatment ofa selected condition in a patient. In some embodiments, active compoundsare administered at a therapeutically effective dosage sufficient totreat a condition associated with a condition in a patient. For example,the efficacy of a compound can be evaluated in an animal model systemthat may be predictive of efficacy in treating the disease in a human oranother animal.

In some embodiments, the effective dose range for the therapeuticcompound can be extrapolated from effective doses determined in animalstudies for a variety of different animals. In some embodiments, thehuman equivalent dose (HED) in mg/kg can be calculated in accordancewith the following formula (see, e.g., Reagan-Shaw et al., FASEB J.,22(3):659-661, 2008, which is incorporated herein by reference):

HED (mg/kg)=Animal dose (mg/kg)×(Animal K _(m)/Human K _(m))

Use of the K_(m) factors in conversion results in HED values based onbody surface area (BSA) rather than only on body mass. K_(m) values forhumans and various animals are well known. For example, the K_(m) for anaverage 60 kg human (with a BSA of 1.6 m²) is 37, whereas a 20 kg child(BSA 0.8 m²) would have a K_(m) of 25. K_(m) for some relevant animalmodels are also well known, including: mice K_(m) of 3 (given a weightof 0.02 kg and BSA of 0.007); hamster K_(m) of 5 (given a weight of 0.08kg and BSA of 0.02); rat K_(m) of 6 (given a weight of 0.15 kg and BSAof 0.025) and monkey K_(m) of 12 (given a weight of 3 kg and BSA of0.24).

Precise amounts of the therapeutic composition depend on the judgment ofthe practitioner and are specific to each individual. Nonetheless, acalculated HED dose provides a general guide. Other factors affectingthe dose include the physical and clinical state of the patient, theroute of administration, the intended goal of treatment and the potency,stability and toxicity of the particular therapeutic formulation.

The actual dosage amount of a compound of the present disclosure orcomposition comprising a compound of the present disclosure administeredto a patient may be determined by physical and physiological factorssuch as type of animal treated, age, sex, body weight, severity ofcondition, the type of disease being treated, previous or concurrenttherapeutic interventions, idiopathy of the patient and on the route ofadministration. These factors may be determined by a skilled artisan.The practitioner responsible for administration will typically determinethe concentration of active ingredient(s) in a composition andappropriate dose(s) for the individual patient. The dosage may beadjusted by the individual physician in the event of any complication.

In some embodiments, the therapeutically effective amount typically willvary from about 0.001 mg/kg to about 1000 mg/kg, from about 0.01 mg/kgto about 750 mg/kg, from about 100 mg/kg to about 500 mg/kg, from about1 mg/kg to about 250 mg/kg, from about 10 mg/kg to about 150 mg/kg inone or more dose administrations daily, for one or several days(depending of course of the mode of administration and the factorsdiscussed above). Other suitable dose ranges include 1 mg to 10,000 mgper day, 100 mg to 10,000 mg per day, 500 mg to 10,000 mg per day, and500 mg to 1,000 mg per day. In some embodiments, the amount is less than10,000 mg per day with a range of 750 mg to 9,000 mg per day.

In some embodiments, the amount of the active compound in thepharmaceutical formulation is from about 2 to about 75 weight percent.In some of these embodiments, the amount if from about 25 to about 60weight percent.

Single or multiple doses of the agents are contemplated. Desired timeintervals for delivery of multiple doses can be determined by one ofordinary skill in the art employing no more than routineexperimentation. As an example, patients may be administered two dosesdaily at approximately 12-hour intervals. In some embodiments, the agentis administered once a day.

The agent(s) may be administered on a routine schedule. As used herein aroutine schedule refers to a predetermined designated period of time.The routine schedule may encompass periods of time which are identical,or which differ in length, as long as the schedule is predetermined. Forinstance, the routine schedule may involve administration twice a day,every day, every two days, every three days, every four days, every fivedays, every six days, a weekly basis, a monthly basis or any set numberof days or weeks there-between. Alternatively, the predetermined routineschedule may involve administration on a twice daily basis for the firstweek, followed by a daily basis for several months, etc. In otherembodiments, the invention provides that the agent(s) may be takenorally and that the timing of which is or is not dependent upon foodintake. Thus, for example, the agent can be taken every morning and/orevery evening, regardless of when the patient has eaten or will eat.

IV. COMBINATION THERAPY

In addition to being used as a monotherapy, the compounds of the presentinvention may also find use in combination therapies. Effectivecombination therapy may be achieved with a single composition orpharmacological formulation that includes both agents, or with twodistinct compositions or formulations, administered at the same time,wherein one composition includes a compound of this invention, and theother includes the second agent(s). Alternatively, the therapy mayprecede or follow the other agent treatment by intervals ranging fromminutes to months.

Non-limiting examples of such combination therapy include combination ofone or more compounds of the invention with another anti-inflammatoryagent, a chemotherapeutic agent, radiation therapy, an antidepressant,an antipsychotic agent, an anticonvulsant, a mood stabilizer, ananti-infective agent, an antihypertensive agent, a cholesterol-loweringagent or other modulator of blood lipids, an agent for promoting weightloss, an antithrombotic agent, an agent for treating or preventingcardiovascular events such as myocardial infarction or stroke, anantidiabetic agent, an agent for reducing transplant rejection orgraft-versus-host disease, an anti-arthritic agent, an analgesic agent,an anti-asthmatic agent or other treatment for respiratory diseases, oran agent for treatment or prevention of skin disorders. Compounds of theinvention may be combined with agents designed to improve a patient'simmune response to cancer, including (but not limited to) cancervaccines. See Lu et al. (2011), which is incorporated herein byreference.

V. DEFINITIONS

When used in the context of a chemical group: “hydrogen” means H;“hydroxy” means —OH; “oxo” means ═O; “carbonyl” means —C(═O)—; “carboxy”means —C(═O)OH (also written as —COOH or —CO₂H); “halo” meansindependently —F, —Cl, —Br or —I; “amino” means —NH₂; “hydroxyamino”means —NHOH; “nitro” means —NO₂; imino means ═NH; “cyano” means —CN;“isocyanyl” means —N═C═O; “azido” means —N₃; in a monovalent context“phosphate” means —OP(O)(OH)₂ or a deprotonated form thereof; in adivalent context “phosphate” means —OP(O)(OH)O— or a deprotonated formthereof; “mercapto” means SH; and “thio” means ═S; “sulfonyl” means—S(O)₂—; and “sulfinyl” means —S(O)—.

In the context of chemical formulas, the symbol “—” means a single bond,“═” means a double bond, and “≡” means triple bond. The symbol “----”represents an optional bond, which if present is either single ordouble. The symbol “

” represents a single bond or a double bond. Additionally, this symbolmay be used to refer to an epoxidized double bond such as the groupfound in the compounds described in PCT/US2013/045975 (WO 2013/188818),the entire contents of which are hereby incorporated by reference. Thus,the formula

covers, for example,

And it is understood that no one such ring atom forms part of more thanone double bond. Furthermore, it is noted that the covalent bond symbol“—”, when connecting one or two stereogenic atoms, does not indicate anypreferred stereochemistry. Instead, it covers all stereoisomers as wellas mixtures thereof. The symbol “

”, when drawn perpendicularly across a bond (e.g.,

for methyl) indicates a point of attachment of the group. It is notedthat the point of attachment is typically only identified in this mannerfor larger groups in order to assist the reader in unambiguouslyidentifying a point of attachment. The symbol “

” means a single bond where the group attached to the thick end of thewedge is “out of the page.” The symbol “

” means a single bond where the group attached to the thick end of thewedge is “into the page”. The symbol “

” means a single bond where the geometry around a double bond (e.g.,either E or Z) is undefined. Both options, as well as combinationsthereof are therefore intended. Any undefined valency on an atom of astructure shown in this application implicitly represents a hydrogenatom bonded to that atom. A bold dot on a carbon atom indicates that thehydrogen attached to that carbon is oriented out of the plane of thepaper.

When a variable is depicted as a “floating group” on a ring system, forexample, the group “R” in the formula:

then the variable may replace any hydrogen atom attached to any of thering atoms, including a depicted, implied, or expressly definedhydrogen, so long as a stable structure is formed. When a variable isdepicted as a “floating group” on a fused ring system, as for examplethe group “R” in the formula:

then the variable may replace any hydrogen attached to any of the ringatoms of either of the fused rings unless specified otherwise.Replaceable hydrogens include depicted hydrogens (e.g., the hydrogenattached to the nitrogen in the formula above), implied hydrogens (e.g.,a hydrogen of the formula above that is not shown but understood to bepresent), expressly defined hydrogens, and optional hydrogens whosepresence depends on the identity of a ring atom (e.g., a hydrogenattached to group X, when X equals —CH—), so long as a stable structureis formed. In the example depicted, R may reside on either the5-membered or the 6-membered ring of the fused ring system. In theformula above, the subscript letter “y” immediately following the Renclosed in parentheses, represents a numeric variable. Unless specifiedotherwise, this variable can be 0, 1, 2, or any integer greater than 2,only limited by the maximum number of replaceable hydrogen atoms of thering or ring system.

For the chemical groups and compound classes, the number of carbon atomsin the group or class is as indicated as follows: “Cn” defines the exactnumber (n) of carbon atoms in the group/class. “C≤n” defines the maximumnumber (n) of carbon atoms that can be in the group/class, with theminimum number as small as possible for the group/class in question. Forexample, it is understood that the minimum number of carbon atoms in thegroups “alkyl_((C≤8))”, “cycloalkanediyl_((C≤8))”, “heteroaryl_((C≤8))”,and “acyl_((C≤8))” is one, the minimum number of carbon atoms in thegroups “alkenyl_((C≤8))”, “alkynyl_((C≤8))”, and“heterocycloalkyl_((C≤8))” is two, the minimum number of carbon atoms inthe group “cycloalkyl_((C≤8))” is three, and the minimum number ofcarbon atoms in the groups “aryl_((C≤8))” and “arenediyl_((C≤8))” issix. “Cn-n′” defines both the minimum (n) and maximum number (n′) ofcarbon atoms in the group. Thus, “alkyl_((C2-10))” designates thosealkyl groups having from 2 to 10 carbon atoms. These carbon numberindicators may precede or follow the chemical groups or class itmodifies and it may or may not be enclosed in parenthesis, withoutsignifying any change in meaning. Thus, the terms “C5 olefin”,“C5-olefin”, “olefin_((C5))”, and “olefincs” are all synonymous. Whenany of the chemical groups or compound classes defined herein ismodified by the term “substituted”, any carbon atom in the moietyreplacing the hydrogen atom is not counted. Thus methoxyhexyl, which hasa total of seven carbon atoms, is an example of a substitutedalkyl_((C1-6)). Unless specified otherwise, any chemical group orcompound class listed in a claim set without a carbon atom limit has acarbon atom limit of less than or equal to twelve.

The term “saturated” when used to modify a compound or chemical groupmeans the compound or chemical group has no carbon-carbon double and nocarbon-carbon triple bonds, except as noted below. When the term is usedto modify an atom, it means that the atom is not part of any double ortriple bond. In the case of substituted versions of saturated groups,one or more carbon oxygen double bond or a carbon nitrogen double bondmay be present. And when such a bond is present, then carbon-carbondouble bonds that may occur as part of keto-enol tautomerism orimine/enamine tautomerism are not precluded. When the term “saturated”is used to modify a solution of a substance, it means that no more ofthat substance can dissolve in that solution.

The term “aliphatic” signifies that the compound or chemical group somodified is an acyclic or cyclic, but non-aromatic compound or group. Inaliphatic compounds/groups, the carbon atoms can be joined together instraight chains, branched chains, or non-aromatic rings (alicyclic).Aliphatic compounds/groups can be saturated, that is joined by singlecarbon-carbon bonds (alkanes/alkyl), or unsaturated, with one or morecarbon-carbon double bonds (alkenes/alkenyl) or with one or morecarbon-carbon triple bonds (alkynes/alkynyl).

The term “aromatic” signifies that the compound or chemical group somodified has a planar unsaturated ring of atoms with 4n+2 electrons in afully conjugated cyclic π system.

The term “alkyl” refers to a monovalent saturated aliphatic group with acarbon atom as the point of attachment, a linear or branched acyclicstructure, and no atoms other than carbon and hydrogen. The groups —CH₃(Me), —CH₂CH₃ (Et), —CH₂CH₂CH₃ (n-Pr or propyl), —CH(CH₃)₂, (i-Pr,^(i)Pr or isopropyl), —CH₂CH₂CH₂CH₃ (n-Bu), —CH(CH₃)CH₂CH₃ (sec-butyl),—CH₂CH(CH₃)₂ (isobutyl), —C(CH₃)₃ (tert-butyl, t-butyl, t-Bu or ^(t)Bu),and —CH₂C(CH₃)₃ (neo-pentyl) are non-limiting examples of alkyl groups.The term “alkanediyl” refers to a divalent saturated aliphatic group,with one or two saturated carbon atom(s) as the point(s) of attachment,a linear or branched acyclic structure, no carbon-carbon double ortriple bonds, and no atoms other than carbon and hydrogen. The groups—CH₂— (methylene), —CH₂CH₂—, —CH₂C(CH₃)₂CH₂—, and —CH₂CH₂CH₂— arenon-limiting examples of alkanediyl groups. The term “alkylidene” refersto the divalent group ═CRR′ in which R and R′ are independentlyhydrogen, alkyl, aryl, or heteroaryl. Non-limiting examples ofalkylidene groups include: ═CH₂, ═CH(CH₂CH₃), and ═C(CH₃)₂. An “alkane”refers to the class of compounds having the formula HR, wherein R isalkyl as this term is defined above.

The term “cycloalkyl” refers to a monovalent saturated aliphatic groupwith a carbon atom as the point of attachment, said carbon atom formingpart of one or more non-aromatic ring structures, no carbon-carbondouble or triple bonds, and no atoms other than carbon and hydrogen.Non-limiting examples include: —CH(CH₂)₂ (cyclopropyl), cyclobutyl,cyclopentyl, or cyclohexyl (Cy). As used herein, the term does notpreclude the presence of one or more alkyl groups (carbon numberlimitation permitting) attached to a carbon atom of the non-aromaticring structure. The term “cycloalkanediyl” refers to a divalentsaturated aliphatic group with two carbon atoms as points of attachment,no carbon-carbon double or triple bonds, and no atoms other than carbonand hydrogen. The group

is a non-limiting example of cycloalkanediyl group. A “cycloalkane”refers to the class of compounds having the formula H—R, wherein R iscycloalkyl as this term is defined above.

The term “alkenyl” refers to a monovalent unsaturated aliphatic groupwith a carbon atom as the point of attachment, a linear or branched,acyclic structure, at least one nonaromatic carbon-carbon double bond,no carbon-carbon triple bonds, and no atoms other than carbon andhydrogen. Non-limiting examples include: —CH═CH₂ (vinyl), —CH═CHCH₃,—CH═CHCH₂CH₃, —CH₂CH═CH₂ (allyl), —CH₂CH═CHCH₃, and —CH═CHCH═CH₂. Theterm “alkenediyl” refers to a divalent unsaturated aliphatic group, withtwo carbon atoms as points of attachment, a linear or branched acyclicstructure, at least one nonaromatic carbon-carbon double bond, nocarbon-carbon triple bonds, and no atoms other than carbon and hydrogen.The groups —CH═CH—, —CH═C(CH₃)CH₂—, —CH═CHCH₂—, and —CH₂CH═CHCH₂— arenon-limiting examples of alkenediyl groups. It is noted that while thealkenediyl group is aliphatic, once connected at both ends, this groupis not precluded from forming part of an aromatic structure. The terms“alkene” and “olefin” are synonymous and refer to the class of compoundshaving the formula H—R, wherein R is alkenyl as this term is definedabove. Similarly, the terms “terminal alkene” and “α-olefin” aresynonymous and refer to an alkene having just one carbon-carbon doublebond, wherein that bond is part of a vinyl group at an end of themolecule.

The term “alkynyl” refers to a monovalent unsaturated aliphatic groupwith a carbon atom as the point of attachment, a linear or branchedacyclic structure, at least one carbon-carbon triple bond, and no atomsother than carbon and hydrogen. As used herein, the term alkynyl doesnot preclude the presence of one or more non-aromatic carbon-carbondouble bonds. The groups —C≡CH, —C≡CCH₃, and —CH₂C≡CCH₃ are non-limitingexamples of alkynyl groups. An “alkyne” refers to the class of compoundshaving the formula H—R, wherein R is alkynyl.

The term “aryl” refers to a monovalent unsaturated aromatic group withan aromatic carbon atom as the point of attachment, said carbon atomforming part of a one or more aromatic ring structures, each with sixring atoms that are all carbon, and wherein the group consists of noatoms other than carbon and hydrogen. If more than one ring is present,the rings may be fused or unfused. Unfused rings are connected with acovalent bond. As used herein, the term aryl does not preclude thepresence of one or more alkyl, aryl, or aralkyl groups (carbon numberlimitation permitting) attached to the first aromatic ring or anyadditional aromatic ring present. Non-limiting examples of aryl groupsinclude phenyl (Ph), methylphenyl, (dimethyl)phenyl, —C₆H₄CH₂CH₃(ethylphenyl), naphthyl, and a monovalent group derived from biphenyl(e.g., 4-phenylphenyl). The term “arenediyl” refers to a divalentaromatic group with two aromatic carbon atoms as points of attachment,said carbon atoms forming part of one or more six-membered aromatic ringstructures, each with six ring atoms that are all carbon, and whereinthe divalent group consists of no atoms other than carbon and hydrogen.As used herein, the term arenediyl does not preclude the presence of oneor more alkyl groups (carbon number limitation permitting) attached tothe first aromatic ring or any additional aromatic ring present. If morethan one ring is present, the rings may be fused or unfused. Unfusedrings are connected with a covalent bond. Non-limiting examples ofarenediyl groups include:

An “arene” refers to the class of compounds having the formula HR,wherein R is aryl as that term is defined above. Benzene and toluene arenon-limiting examples of arenes.

The term “aralkyl” refers to the monovalent group -alkanediyl-aryl, inwhich the terms alkanediyl and aryl are each used in a manner consistentwith the definitions provided above. Non-limiting examples are:phenylmethyl (benzyl, Bn) and 2-phenyl-ethyl.

The term “heteroaryl” refers to a monovalent aromatic group with anaromatic carbon atom or nitrogen atom as the point of attachment, saidcarbon atom or nitrogen atom forming part of one or more aromatic ringstructures, each with three to eight ring atoms, wherein at least one ofthe ring atoms of the aromatic ring structure(s) is nitrogen, oxygen orsulfur, and wherein the heteroaryl group consists of no atoms other thancarbon, hydrogen, aromatic nitrogen, aromatic oxygen and aromaticsulfur. If more than one ring is present, the rings are fused. The termheteroaryl does not preclude the presence of one or more alkyl,cycloalkyl, heterocycloalkyl, aryl, or aralkyl groups (carbon numberlimitation permitting) attached to one or more ring atoms. Non-limitingexamples of heteroaryl groups include benzthiazolyl, benzimidazolyl,furanyl, imidazolyl (Im), indolyl, indazolyl (Im), isoxazolyl,methylpyridinyl, oxazolyl, phenylpyridinyl, pyridinyl (pyridyl),pyrrolyl, pyrimidinyl, pyrazinyl, quinolyl, quinazolyl, quinoxalinyl,triazinyl, tetrazolyl, thiazolyl, thienyl, and triazolyl. The term“N-heteroaryl” refers to a heteroaryl group with a nitrogen atom as thepoint of attachment. A “heteroarene” refers to the class of compoundshaving the formula H—R, wherein R is heteroaryl. Pyridine and quinolineare non-limiting examples of heteroarenes.

The term “heteroarenediyl” refers to a divalent aromatic group, with twoaromatic carbon atoms, two aromatic nitrogen atoms, or one aromaticcarbon atom and one aromatic nitrogen atom as the two points ofattachment, said atoms forming part of one or more aromatic ringstructures, each with three to eight ring atoms, wherein at least one ofthe ring atoms of the aromatic ring structure(s) is nitrogen, oxygen orsulfur, and wherein the divalent group consists of no atoms other thancarbon, hydrogen, aromatic nitrogen, aromatic oxygen and aromaticsulfur. If more than one ring is present, the rings are fused; however,the term heteroarenediyl does not preclude the presence of one or morealkyl or aryl groups (carbon number limitation permitting) attached toone or more ring atoms. Non-limiting examples of heteroarenediyl groupsinclude:

The term “heteroaralkyl” refers to the monovalent group-alkanediyl-heteroaryl, in which the terms alkanediyl and heteroaryl areeach used in a manner consistent with the definitions provided above.Non-limiting examples are: pyridinylmethyl and 2-quinolinyl-ethyl.

The term “heterocycloalkyl” refers to a monovalent non-aromatic groupwith a carbon atom or nitrogen atom as the point of attachment, saidcarbon atom or nitrogen atom forming part of one or more non-aromaticring structures, each with three to eight ring atoms, wherein at leastone of the ring atoms of the non-aromatic ring structure(s) is nitrogen,oxygen or sulfur, and wherein the heterocycloalkyl group consists of noatoms other than carbon, hydrogen, nitrogen, oxygen and sulfur. If morethan one ring is present, the rings are fused. As used herein, the termdoes not preclude the presence of one or more alkyl or cycloalkyl groups(carbon number limitation permitting) attached to one or more ringatoms. Also, the term does not preclude the presence of one or moredouble bonds in the ring or ring system, provided that the resultinggroup remains non-aromatic. Non-limiting examples of heterocycloalkylgroups include aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl,tetrahydrothiofuranyl, tetrahydropyranyl, pyranyl, oxiranyl, andoxetanyl. The term “N-heterocycloalkyl” refers to a heterocycloalkylgroup with a nitrogen atom as the point of attachment. N-pyrrolidinyl isan example of such a group.

The term “heterocycloalkanediyl” refers to a divalent cyclic group, withtwo carbon atoms, two nitrogen atoms, or one carbon atom and onenitrogen atom as the two points of attachment, said atoms forming partof one or more ring structure(s) wherein at least one of the ring atomsof the non-aromatic ring structure(s) is nitrogen, oxygen or sulfur, andwherein the divalent group consists of no atoms other than carbon,hydrogen, nitrogen, oxygen and sulfur. If more than one ring is present,the rings are fused. As used herein, the term heterocycloalkanediyl doesnot preclude the presence of one or more alkyl groups (carbon numberlimitation permitting) attached to one or more ring atoms. Also, theterm does not preclude the presence of one or more double bonds in thering or ring system, provided that the resulting group remainsnon-aromatic. Non-limiting examples of heterocycloalkanediyl groupsinclude:

The term “acyl” refers to the group —C(O)R, in which R is a hydrogen,alkyl, cycloalkyl, or aryl as those terms are defined above. The groups,—CHO, —C(O)CH₃ (acetyl, Ac), —C(O)CH₂CH₃, —C(O)CH(CH₃)₂, —C(O)CH(CH₂)₂,—C(O)C₆H₅, and —C(O)C₆H₄CH₃ are non-limiting examples of acyl groups. A“thioacyl” is defined in an analogous manner, except that the oxygenatom of the group —C(O)R has been replaced with a sulfur atom, —C(S)R.The term “aldehyde” corresponds to an alkyl group, as defined above,attached to a —CHO group.

The term “alkoxy” refers to the group —OR, in which R is an alkyl, asthat term is defined above. Non-limiting examples include: —OCH₃(methoxy), —OCH₂CH₃ (ethoxy), —OCH₂CH₂CH₃, —OCH(CH₃)₂ (isopropoxy), orOC(CH₃)₃ (tert-butoxy). The terms “cycloalkoxy”, “alkenyloxy”,“alkynyloxy”, “aryl oxy”, “aralkoxy”, “heteroaryloxy”,“heterocycloalkoxy”, and “acyloxy”, when used without the “substituted”modifier, refers to groups, defined as —OR, in which R is cycloalkyl,alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocycloalkyl, and acyl,respectively. The term “alkylthio” and “acylthio” refers to the group—SR, in which R is an alkyl and acyl, respectively. The term “alcohol”corresponds to an alkane, as defined above, wherein at least one of thehydrogen atoms has been replaced with a hydroxy group. The term “ether”corresponds to an alkane, as defined above, wherein at least one of thehydrogen atoms has been replaced with an alkoxy group.

The term “alkylamino” refers to the group —NHR, in which R is an alkyl,as that term is defined above. Non-limiting examples include: —NHCH₃ and—NHCH₂CH₃. The term “dialkylamino” refers to the group —NRR′, in which Rand R′ can be the same or different alkyl groups. Non-limiting examplesof dialkylamino groups include: —N(CH₃)₂ and —N(CH₃)(CH₂CH₃). The terms“cycloalkylamino”, “alkenylamino”, “alkynylamino”, “arylamino”,“aralkylamino”, “heteroarylamino”, “heterocycloalkylamino”,“alkoxyamino”, and “alkylsulfonylamino” when used without the“substituted” modifier, refers to groups, defined as —NHR, in which R iscycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl,heterocycloalkyl, alkoxy, and alkylsulfonyl, respectively. Anon-limiting example of an arylamino group is —NHC₆H₅. The terms“dicycloalkylamino”, “dialkenylamino”, “dialkynylamino”, “diarylamino”,“diaralkylamino”, “diheteroarylamino”, “diheterocycloalkylamino”, and“dialkoxyamino”, refers to groups, defined as —NRR′, in which R and R′are both cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl,heterocycloalkyl, and alkoxy, respectively. Similarly, the termalkyl(cycloalkyl)amino refers to a group defined as —NRR′, in which R isalkyl and R′ is cycloalkyl. The term “amido” (acylamino), when usedwithout the “substituted” modifier, refers to the group —NHR, in which Ris acyl, as that term is defined above. A non-limiting example of anamido group is —NHC(O)CH₃.

The terms “alkylsulfonyl” refers to the group: —S(O)₂R, in which R is analkyl, as that term is defined above. The terms “cycloalkylsulfonyl”,“alkenylsulfonyl”, “alkynylsulfonyl”, “aryl sulfonyl”,“aralkylsulfonyl”, “heteroarylsulfonyl”, “heterocycloalkylsulfonyl”, and“alkoxysulfonyl” are defined in an analogous manner, wherein R is acycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl,heterocycloalkyl, and alkoxy group, respectively, as those terms aredefined above.

When a chemical group is used with the “substituted” modifier, one ormore hydrogen atom has been replaced, independently at each instance, by—OH, —F, —Cl, —Br, —I, —NH₂, —NO₂, —CO₂H, —C(O)H, —CO₂CH₃, —CN, —SH,—OCH₃, —OCH₂CH₃, —C(O)CH₃, —NHCH₃, —NHCH₂CH₃, —N(CH₃)₂, —C(O)NH₂,—C(O)NHCH₃, —C(O)N(CH₃)₂, —OC(O)CH₃, —NHC(O)CH₃, —S(O)₂CH₃, —S(O)₂OH, or—S(O)₂NH₂. For example, the following groups are non-limiting examplesof substituted alkyl groups: —CH₂OH, —CH₂Cl, —CF₃, —CH₂CN, —CH₂C(O)OH,—CH₂C(O)OCH₃, —CH₂C(O)NH₂, —CH₂C(O)CH₃, —CH₂OCH₃, —CH₂OC(O)CH₃, —CH₂NH₂,—CH₂N(CH₃)₂, and —CH₂CH₂Cl. The term “haloalkyl” is a subset ofsubstituted alkyl, in which the hydrogen atom replacement is limited tohalo (i.e. —F, —Cl, —Br, or —I) such that no other atoms aside fromcarbon, hydrogen and halogen are present. The group, —CH₂Cl is anon-limiting example of a haloalkyl. The term “fluoroalkyl” is a subsetof substituted alkyl, in which the hydrogen atom replacement is limitedto fluoro such that no other atoms aside from carbon, hydrogen andfluorine are present. The groups —CH₂F, —CF₃, and —CH₂CF₃ arenon-limiting examples of fluoroalkyl groups. Non-limiting examples ofsubstituted aralkyls are: (3-chlorophenyl)-methyl, and2-chloro-2-phenyl-eth-1-yl. The groups, —C(O)CH₂CF₃, —CO₂H (carboxyl),—CO₂CH₃ (methylcarboxyl), —CO₂CH₂CH₃, —C(O)NH₂ (carbamoyl), and—CON(CH₃)₂, are non-limiting examples of substituted acyl groups. Thegroups —NHC(O)OCH₃ and —NHC(O)NHCH₃ are non-limiting examples ofsubstituted amido groups.

The use of the word “a” or “an,” when used in conjunction with the term“comprising” in the claims and/or the specification may mean “one,” butit is also consistent with the meaning of “one or more,” “at least one,”and “one or more than one.”

Throughout this application, the term “about” is used to indicate that avalue includes the inherent variation of error for the device, themethod being employed to determine the value, or the variation thatexists among the study subjects or patients.

An “active ingredient” (AI) or active pharmaceutical ingredient (API)(also referred to as an active compound, active substance, active agent,pharmaceutical agent, agent, biologically active molecule, or atherapeutic compound) is the ingredient in a pharmaceutical drug that isbiologically active.

The terms “comprise,” “have” and “include” are open-ended linking verbs.Any forms or tenses of one or more of these verbs, such as “comprises,”“comprising,” “has,” “having,” “includes” and “including,” are alsoopen-ended. For example, any method that “comprises,” “has” or“includes” one or more steps is not limited to possessing only those oneor more steps and also covers other unlisted steps.

The term “effective,” as that term is used in the specification and/orclaims, means adequate to accomplish a desired, expected, or intendedresult. “Effective amount,” “Therapeutically effective amount” or“pharmaceutically effective amount” when used in the context of treatinga patient or subject with a compound means that amount of the compoundwhich, when administered to a subject or patient for treating orpreventing a disease, is an amount sufficient to effect such treatmentor prevention of the disease.

An “excipient” is a pharmaceutically acceptable substance formulatedalong with the active ingredient(s) of a medication, pharmaceuticalcomposition, formulation, or drug delivery system. Excipients may beused, for example, to stabilize the composition, to bulk up thecomposition (thus often referred to as “bulking agents,” “fillers,” or“diluents” when used for this purpose), or to confer a therapeuticenhancement on the active ingredient in the final dosage form, such asfacilitating drug absorption, reducing viscosity, or enhancingsolubility. Excipients include pharmaceutically acceptable versions ofantiadherents, binders, coatings, colors, disintegrants, flavors,glidants, lubricants, preservatives, sorbents, sweeteners, and vehicles.The main excipient that serves as a medium for conveying the activeingredient is usually called the vehicle. Excipients may also be used inthe manufacturing process, for example, to aid in the handling of theactive substance, such as by facilitating powder flowability ornon-stick properties, in addition to aiding in vitro stability such asprevention of denaturation or aggregation over the expected shelf life.The suitability of an excipient will typically vary depending on theroute of administration, the dosage form, the active ingredient, as wellas other factors.

The term “hydrate” when used as a modifier to a compound means that thecompound has less than one (e.g., hemihydrate), one (e.g., monohydrate),or more than one (e.g., dihydrate) water molecules associated with eachcompound molecule, such as in solid forms of the compound.

As used herein, the term “IC₅₀” refers to an inhibitory dose which is50% of the maximum response obtained. This quantitative measureindicates how much of a particular drug or other substance (inhibitor)is needed to inhibit a given biological, biochemical or chemical process(or component of a process, i.e. an enzyme, cell, cell receptor ormicroorganism) by half.

An “isomer” of a first compound is a separate compound in which eachmolecule contains the same constituent atoms as the first compound, butwhere the configuration of those atoms in three dimensions differs.

As used herein, the term “patient” or “subject” refers to a livingmammalian organism, such as a human, monkey, cow, sheep, goat, dog, cat,mouse, rat, guinea pig, or transgenic species thereof. In certainembodiments, the patient or subject is a primate. Non-limiting examplesof human patients are adults, juveniles, infants and fetuses.

As generally used herein “pharmaceutically acceptable” refers to thosecompounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues, organs, and/or bodily fluids of human beings andanimals without excessive toxicity, irritation, allergic response, orother problems or complications commensurate with a reasonablebenefit/risk ratio. One example of compounds which are pharmaceuticallyacceptable include those compounds, materials, compositions, and/ordosage forms have been designated by the United States Food and DrugAdministration (US FDA) as having a status of generally regarded as safe(GRAS).

“Pharmaceutically acceptable salts” means salts of compounds disclosedherein which are pharmaceutically acceptable, as defined above, andwhich possess the desired pharmacological activity. Such salts includeacid addition salts formed with inorganic acids such as hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, andthe like; or with organic acids such as 1,2-ethanedisulfonic acid,2-hydroxyethanesulfonic acid, 2-naphthalenesulfonic acid,3-phenylpropionic acid, 4,4′-methylenebis(3-hydroxy-2-ene-1-carboxylicacid), 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, acetic acid,aliphatic mono- and dicarboxylic acids, aliphatic sulfuric acids,aromatic sulfuric acids, benzenesulfonic acid, benzoic acid,camphorsulfonic acid, carbonic acid, cinnamic acid, citric acid,cyclopentanepropionic acid, ethanesulfonic acid, fumaric acid,glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid,heptanoic acid, hexanoic acid, hydroxynaphthoic acid, lactic acid,laurylsulfuric acid, maleic acid, malic acid, malonic acid, mandelicacid, methanesulfonic acid, muconic acid, o-(4-hydroxybenzoyl)benzoicacid, oxalic acid, p-chlorobenzenesulfonic acid, phenyl-substitutedalkanoic acids, propionic acid, p-toluenesulfonic acid, pyruvic acid,salicylic acid, stearic acid, succinic acid, tartaric acid,tertiarybutylacetic acid, trimethylacetic acid, and the like.Pharmaceutically acceptable salts also include base addition salts whichmay be formed when acidic protons present are capable of reacting withinorganic or organic bases. Acceptable inorganic bases include sodiumhydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide andcalcium hydroxide. Acceptable organic bases include ethanolamine,diethanolamine, triethanolamine, tromethamine, N-methylglucamine and thelike. It should be recognized that the particular anion or cationforming a part of any salt of this invention is not critical, so long asthe salt, as a whole, is pharmacologically acceptable. Additionalexamples of pharmaceutically acceptable salts and their methods ofpreparation and use are presented in Handbook of Pharmaceutical Salts:Properties, and Use (P. H. Stahl & C. G. Wermuth eds., Verlag HelveticaChimica Acta, 2002).

A “pharmaceutically acceptable carrier,” “drug carrier,” or simply“carrier” is a pharmaceutically acceptable substance formulated alongwith the active ingredient medication that is involved in carrying,delivering and/or transporting a chemical agent. Drug carriers may beused to improve the delivery and the effectiveness of drugs, includingfor example, controlled-release technology to modulate drugbioavailability, decrease drug metabolism, and/or reduce drug toxicity.Some drug carriers may increase the effectiveness of drug delivery tothe specific target sites. Examples of carriers include: liposomes,microspheres (e.g., made of poly(lactic-co-glycolic) acid), albuminmicrospheres, synthetic polymers, nanofibers, protein-DNA complexes,protein conjugates, erythrocytes, virosomes, and dendrimers.

A “pharmaceutical drug” (also referred to as a pharmaceutical,pharmaceutical preparation, pharmaceutical composition, pharmaceuticalformulation, pharmaceutical product, medicinal product, medicine,medication, medicament, or simply a drug, agent, or preparation) is acomposition used to diagnose, cure, treat, or prevent disease, whichcomprises an active pharmaceutical ingredient (API) (defined above) andoptionally contains one or more inactive ingredients, which are alsoreferred to as excipients (defined above).

“Prevention” or “preventing” includes: (1) inhibiting the onset of adisease in a subject or patient which may be at risk and/or predisposedto the disease but does not yet experience or display any or all of thepathology or symptomatology of the disease, and/or (2) slowing the onsetof the pathology or symptomatology of a disease in a subject or patientwhich may be at risk and/or predisposed to the disease but does not yetexperience or display any or all of the pathology or symptomatology ofthe disease.

“Prodrug” means a compound that is convertible in vivo metabolicallyinto an inhibitor according to the present invention. The prodrug itselfmay or may not also have activity with respect to a given targetprotein. For example, a compound comprising a hydroxy group may beadministered as an ester that is converted by hydrolysis in vivo to thehydroxy compound. Non-limiting examples of suitable esters that may beconverted in vivo into hydroxy compounds include acetates, citrates,lactates, phosphates, tartrates, malonates, oxalates, salicylates,propionates, succinates, fumarates, maleates,methylene-bis-β-hydroxynaphthoate, gentisates, isethionates,di-p-toluoyltartrates, methanesulfonates, ethanesulfonates,benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates, quinates,and esters of amino acids. Similarly, a compound comprising an aminegroup may be administered as an amide that is converted by hydrolysis invivo to the amine compound.

A “stereoisomer” or “optical isomer” is an isomer of a given compound inwhich the same atoms are bonded to the same other atoms, but where theconfiguration of those atoms in three dimensions differs. “Enantiomers”are stereoisomers of a given compound that are mirror images of eachother, like left and right hands. “Diastereomers” are stereoisomers of agiven compound that are not enantiomers. Chiral molecules contain achiral center, also referred to as a stereocenter or stereogenic center,which is any point, though not necessarily an atom, in a moleculebearing groups such that an interchanging of any two groups leads to astereoisomer. In organic compounds, the chiral center is typically acarbon, phosphorus or sulfur atom, though it is also possible for otheratoms to be stereocenters in organic and inorganic compounds. A moleculecan have multiple stereocenters, giving it many stereoisomers. Incompounds whose stereoisomerism is due to tetrahedral stereogeniccenters (e.g., tetrahedral carbon), the total number of hypotheticallypossible stereoisomers will not exceed 2^(n), where n is the number oftetrahedral stereocenters. Molecules with symmetry frequently have fewerthan the maximum possible number of stereoisomers. A 50:50 mixture ofenantiomers is referred to as a racemic mixture. Alternatively, amixture of enantiomers can be enantiomerically enriched so that oneenantiomer is present in an amount greater than 50%. Typically,enantiomers and/or diastereomers can be resolved or separated usingtechniques known in the art. It is contemplated that that for anystereocenter or axis of chirality for which stereochemistry has not beendefined, that stereocenter or axis of chirality can be present in its Rform, S form, or as a mixture of the R and S forms, including racemicand non-racemic mixtures. As used herein, the phrase “substantially freefrom other stereoisomers” means that the composition contains ≤15%, morepreferably ≤10%, even more preferably ≤5%, or most preferably ≤1% ofanother stereoisomer(s).

“Treatment” or “treating” includes (1) inhibiting a disease in a subjector patient experiencing or displaying the pathology or symptomatology ofthe disease (e.g., arresting further development of the pathology and/orsymptomatology), (2) ameliorating a disease in a subject or patient thatis experiencing or displaying the pathology or symptomatology of thedisease (e.g., reversing the pathology and/or symptomatology), and/or(3) effecting any measurable decrease in a disease or symptom thereof ina subject or patient that is experiencing or displaying the pathology orsymptomatology of the disease.

The term “unit dose” refers to a formulation of the compound orcomposition such that the formulation is prepared in a manner sufficientto provide a single therapeutically effective dose of the activeingredient to a patient in a single administration. Such unit doseformulations that may be used include but are not limited to a singletablet, capsule, or other oral formulations, or a single vial with asyringeable liquid or other injectable formulations.

The above definitions supersede any conflicting definition in anyreference that is incorporated by reference herein. The fact thatcertain terms are defined, however, should not be considered asindicative that any term that is undefined is indefinite. Rather, allterms used are believed to describe the invention in terms such that oneof ordinary skill can appreciate the scope and practice the presentinvention.

VI. EXAMPLES

The following examples are included to demonstrate preferred embodimentsof the invention. It should be appreciated by those of skill in the artthat the techniques disclosed in the examples which follow representtechniques discovered by the inventor to function well in the practiceof the invention, and thus can be considered to constitute preferredmodes for its practice. However, those of skill in the art should, inlight of the present disclosure, appreciate that many changes can bemade in the specific embodiments which are disclosed and still obtain alike or similar result without departing from the spirit and scope ofthe invention.

Materials & Methods

RORγ LBD-GAL4 Assay. The RORγ assay system was purchased from IndigoBiosciences (State College, Pa., USA). The assay utilizes a human cellline engineered to provide high level expression of a hybrid form of theHuman RAR-related Orphan Receptor Gamma (RORγ). The N-terminal DNAbinding domain (DBD) of the native RORγ receptor was substituted withthe yeast GAL4-DBD to generate the GAL4-RORγ hybrid nuclear receptor.The reporter cell line is transfected with a plasmid that encodes thebeetle luciferase gene under the control of the GAL4 upstream activatingsequence (UAS). The GAL4-RORγ hybrid is constitutively active providingmeasurable levels of basal Luciferase activity. To assess the RORγinverse-agonist activity of the test compounds, reporter cells wereplated in 96-well plates in triplicate and were treated with DMSO(vehicle) or different concentrations of test compounds at 37° C. with5% CO₂ in a humidified atmosphere for 23 hours. After that, luciferinwas added to the wells and luciferase activity was determined bymeasuring the luminescence signal using a BMG Pherastar microplatereader. Values from test compound samples were normalized to those fromDMSO-treated samples.

Full-length RORgt activity in Jurkat Cells. RORγt transcriptionalactivity was assessed by transfecting human Jurkat T lymphocytes witheach full-length human ROR isoform expression construct together with a5×-RORE luciferase reporter construct and assaying luciferase activity.Expression plasmids consisting of human ROR isoform cDNA in apReceiver-M02 vector were purchased from GeneCopoeia. Specificconstructs included: RORA, transcript variant 1 (Catalog#EX-T3100-M02-B); RORB (Catalog #EX-Z5728-M02-B); and RORC, transcriptvariant 2 (Catalog #EX-T6988-M02-B). The pReceiver-M02 empty vector(Catalog #EX-NEG-M02) was used as control. p5×RORE_sluc3.3 luciferasereporter plasmid was synthesized at Blue Heron Biotech, LLC, byinserting 5 copies of the ROR response element sequence(5′-AAAGTAGGTCA-3′ (SEQ. NO. 3) in XhoI/HindIII restriction sites of thepNL3.3[secNLuc/minP] vector (Promega).

Jurkat cells (Human peripheral blood T lymphocytes) were cultured inRPMI 1640 medium (Life Technologies) supplemented with 10% dilapidatedFBS (Gemini Bio-Products) and 1% penicillin-streptomycin in a humidifiedatmosphere at 37° C. with 5% CO₂. Cells were seeded in a 75 cm² flask ata density of 0.3×106 cells/mL of growth media. After 18 h, cells werere-seeded into 25 cm² flasks at a density of 0.6×106 cells/mL. Cellswere transfected using Lipofectamine LTX with Plus reagent according tothe manufacturer's protocol, with 0.8 μg p5×RORE_sluc3.3 luciferasereporter plasmid and 0.8 μg of pReceiverM02 control, pRORA, pRORB, orpRORC plasmids (1.6 μg plasmid DNA in total) in a total volume of 250 μLOpti-MEM per mL of cell suspension. 6 h after transfection, cells werediluted with growth medium and plated in 96-well plates at a density of5×104 cells per well in 190 μL medium. Immediately following plating,transfected cells were treated for 18 h with vehicle (DMSO) or compoundsat concentrations ranging from 0 to 500 nM in a two-fold dilutionseries. Final DMSO concentration in each well was 0.1%. Three replicatewells were tested for each treatment condition.

NanoLuc luciferase activity was measured using the Nano-Glo LuciferaseAssay System (Promega) according to the manufacturer's protocol.Briefly, after shaking the 96-well plates on an orbital shaker at 100RPM for 2 min and centrifuging at 250×g RPM at room temperature for 5min, 60 μL of media was removed from each well and transferred to thecorresponding well of a 96-well V-bottom plate. Ten (10) μL of thismedia was transferred to duplicate wells of a 384-well Small VolumeHiBase plate, resulting in a total of six luciferase activitymeasurements for each concentration of the test compound. NanoLuc assayreagent (10 μL) was added to each well. After shaking the 384-well plateat 500 RPM for 2 min and incubating at room temperature for anadditional 3 min, the luminescence signal was measured on a PHERAstar FSmicroplate reader (BMG Labtech).

After removing the aliquot of medium for the luciferase assay, 14 μL(10% of remaining volume) WST-1 reagent was added to each well of the96-well plate and incubated at 37° C. with 5% CO₂ for 30 min. MolecularDevices SpectraMax M2e plate reader was used to measure absorbance ofthe formazan dye at 450 nm and background at 650 nm.

IL-17 Release from Th17-polarized Primary Human T-Cells. Primary humancryopreserved CD4+ T Cells (Lonza) were thawed according to themanufacturer's recommendations and plated either in Lymphocyte GrowthMedium-3 (LGM-3) or X-VIVO 20 media (Lonza) in 96-well tissue cultureplates at a density of ˜2×10⁵ cells per well, and allowed to recover forapproximately 4 hours at 37° C. with 5% CO₂ in a humidified atmosphere.After the recovery step, DMSO (vehicle) or test compound at dosesranging from 2 to 500 nM or 4 to 1000 nM in a three-fold dilution serieswas added to the cells. Three replicate wells were tested for eachtreatment condition. Final DMSO concentration in each well was 0.1%.Immediately after treatment, CD4+ T cells were activated by addingDynabeads Human T-Activator CD3/CD28 (Life Technologies; bead-to-cellratio of 1:2.5) and differentiated into Th17 cells by adding a mixtureof the following cytokines: transforming growth factor-β (TGF-β, 5ng/mL), IL-6 (20 ng/mL), IL-23 (20 ng/mL), and IL-1β (10 ng/mL).Undifferentiated control cells received only cytokine IL-2 (50 ng/mL).All human recombinant cytokines were purchased from R&D Systems.Following a 45-hour incubation at 37° C. with 5% CO₂ in a humidifiedatmosphere, the plates were centrifuged for 3 minutes at 250×g, and halfof the supernatant was transferred to a new plate to be used in theIL-17A assay. The concentration of IL-17A in the supernatant wasmeasured using the Homogeneous Time-Resolved Fluorescence (HTRF) assay(Cisbio Bioassays) according to the manufacturer's protocol. The assaywas performed at room temperature in low volume, solid white 384-wellplates (Greiner Bio-One). Samples and standards (serially-diluted humanrecombinant IL-17A (0 to 5,000 μg/mL concentration range; CisbioBioassays) were incubated with the anti-human IL-17A antibody conjugates(the HTRF donor and acceptor pair) for 16 hours and fluorescence wasmeasured using a Pherastar FS microplate reader (BMG Labtech) in theHTRF mode (excitation at 337 nm and emission at 665 nm and 620 nm).IL-17A levels were assessed in duplicate aliquots of supernatant fromeach well resulting in a total of six readings per test condition. The665 nm/620 nm signal ratio was calculated and the concentration ofIL-17A in each sample was determined by interpolation from the standardcurve. The amount of IL-17A from test compound treated samples werenormalized to that of the vehicle-treated samples, set to 100%. Datawere analyzed using GraphPad Prism (GraphPad Software, La Jolla Calif.USA). Concentrations of test compound were transformed by taking thelogarithm of each concentration used. The IC₅₀ values for compoundmediated reduction in IL-17A levels and cell viability were determinedby non-linear regression analysis using the log(inhibitor) vs.normalized response with variable slope equation.

Naïve T cell differentiation and intracellular staining. Naïve CD4+ Tcells were isolated from cryopreserved human PBMCs (ZenBio) using anEasy Sep human naïve CD4+ T cell isolation kit (StemCell Technologies).The purity of cells (CD4+CD45RA+≥95%) was verified by flow cytometry.Naïve cells (2×10⁵ cells/well) were cultured in X-VIVO 20 media (Lonza)in 24-well tissue culture plates pre-coated with anti-CD3 antibody (1μg/mL). Immediately following plating (day 0), cells were treated withvehicle (DMSO) or compound 14 at indicated concentrations. Cells wereactivated with anti-CD28 antibody (1 μg/mL) and cultured for 6 daysunder either neutral (Th0) or Th17-polarizing (Th17) conditions (TGF-β(5 ng/mL), IL-6 (20 ng/mL), IL-1β (10 ng/mL), IL-23 (20 ng/mL),anti-IL-4 antibody (1 μg/mL), and anti-IFN-γ antibody (1 μg/mL)). Allcytokines were from R&D Systems, and all antibodies were from Biolegend.On day 5, cells were resuspended in the same media and reactivated byre-plating in new 24-well plates coated with anti-CD3 antibody (1μg/mL). On day 6, cells were restimulated with Cell Stimulation Cocktail(eBioscience) in the presence of BD GolgiStop™ Protein TransportInhibitor for the last 5 h, stained with Fixable Viability Dye eFluor520 followed by fixation with BD Fixation buffer, permeabilized with BDPerm/Wash buffer and stained with AF647 antihuman IL-17A antibody. Datawere acquired using a BD Accuri™ C6 or C6 Plus flow cytometer (BDBiosciences) and analyzed using FlowJo Software (Tree Star Inc).Lymphocytes were gated based on forward vs. side scatter (FSC vs. SSC)plot. Dead cells were subsequently excluded from analysis based onFixable Viability Dye eFluor520 staining. At least 20,000 events persample were analyzed.

RNA extraction, quantitative RT-PCR. For qPCR analysis, human naïveT-cells were differentiated under Th-17 condition for six days asdescribed under Naïve T cell differentiation and intracellular stainingprotocol. Total RNA was extracted using RNeasy kits including theoptional DNaseI digestion (Qiagen). Following cDNA synthesis, Real Timequantitative PCR was performed on a 7900HT Real Time PCR System (AppliedBiosystems).

Example 1: Activity of RORγ/RORγt Inhibitors

Screening a series of tricyclic compounds in a RORγt-LBD-GAL4 reporterassay, identified the tricyclic pyrimidine 1 with inhibitory activity(IC₅₀=608 nM) (Table 1).

Sequential introduction of C-12 phenyl and 4-pyridyl groups affordedcompound 3 a 9-fold increase in activity relative to 1, with an IC₅₀ of68 nM. Compound 3 was characterized further in a phenotypic assay wherethe amount of IL-17A produced by Th17 polarized human CD4+ T cells wasmeasured. Consistent with the essential role that RORγt plays incontrolling IL-17A expression, potent suppression of IL-17A secretionfrom human CD4+ T-cells treated with compound 3 (IC₅₀=76 nM) wasobserved. The combination of an alkyl substituted C-12 pyridyl ring witha fluoro phenyl C-14 substituent, afforded compounds 12-16 which werequite potent in the RORγt GAL4 transcriptional assay as well as in theIL-17 phenotypic assay (Table 1). Further modification of the A ring, Bring, C4 and C10 was carried out to determine the effects of thesechanges on the potency in the RORγt GAL4 transcriptional assay as wellas in the IL-17 phenotypic assay (Tables 2 and 3).

TABLE 1 Activity of Compound with Modifications at the C12 and C14Positions of the Pyrimidine Ring.

CD4+ T-cell GAL4 IL17 Luc IC₅₀ IC₅₀ Compd R₁ R₂ (μM) (μM)  1 H Phenyl0.071 0.613  2 Phenyl Phenyl 0.030 0.162  3 4′-Pyridyl Phenyl 0.0760.067  4 4′-Pyridyl 4′-Pyridyl 0.128 0.254  5 4′-Pyridyl 3′-Pyridyl0.154 0.212  6 4′-Pyridyl 4′-hydroxy- 0.201 0.203 methylphenyl  74′-Pyridyl Methoxy 0.461 0.163  8 4′-Pyridyl Benzyl 0.132 0.160  9Morpholine 2′-F-Phenyl 0.097 0.136 10 N′-Acetyl piperazine 2′-F-Phenyl0.104 0.141 11 N′-Methyl piperazine 2′-F-Phenyl 0.236 0.314 123′-Methyl-4′-Pyridyl 2′-F-Phenyl 0.048 0.060 13 2′-Methyl-4′-Pyridyl2′-F-Phenyl 0.046 0.060 14 3′-Methyl-4′-Pyridyl 4′-F-Phenyl 0.040 0.05815 3′-Fluoromethyl- 2′-F-Phenyl 0.035 0.074 4′-Pyridyl 163′-Cyclopropyl- 2′-F-Phenyl 0.031 0.097 4′-Pyridyl

TABLE 2 Activity of Compound with Modifications at C4, C10 and theB-ring

GAL4 CD4+ Luciferase T-Cells IL17 Reporter Compd R₁ R₂ B-ring (n) IC₅₀(μM) IC₅₀ (μM) R₃ 16 CH₃ CH₃ cyclohexyl 0.031 0.097 3′-Cyclopropyl (n= 1) 17 CH₃ Phenyl cyclohexyl 0.046 0.475 3′-Cyclopropyl (n = 1) 18 CH₃n-Propyl cyclohexyl 0.026 0.140 3′-Cyclopropyl (n = 1) 19 H iso-Pentylcyclohexyl 0.071 0.402 3′-Fluoromethyl (n = 1) 20 Allyl CH₃ cyclohexyl0.020 0.072 3′-Cyclopropyl (n = 1) 21 n-Propyl CH₃ cyclohexyl 0.0120.082 3′-Cyclopropyl (n = 1) 22 n-Propyl CH₃ cyclohexyl 0.012 0.0923′-CF₃ (n = 1) 23 n-Propyl CH₃ cyclohexyl 0.017 0.051 3′-CH₂F (n = 1) 24CH₃ CH₃ cyclopentyl 0.140 0.334 3′-CH₂F (n = 0) 25 CH₃ CH₃ cyclopentyl0.117 0.524 3′-Cyclopropyl (n = 0) 26 CH₃ CH₃ cycloheptyl 0.076 0.0683′-CH₃ (n = 2)

TABLE 3 Activity of Compound with Modifications at the Michael AcceptorA-ring

CD4+ GAL4 Luc T-cells IL17 Reporter Compd R₁ C1, C2 bond IC₅₀ (μM) IC₅₀(μM) R₂ R₃ R₄  3 CN unsaturated 0.076 0.068 4′-Pyridyl Phenyl Methyl 27CONH₂ unsaturated 0.181 0.337 4′-Pyridyl Phenyl Methyl 14 CN unsaturated0.04 0.058 3′-Methyl-4′-Pyridyl p-Fluorophenyl Methyl 28 CONH₂unsaturated 0.107 0.295 3′-Methyl-4′-Pyridyl p-Fluorophenyl Methyl 21 CNunsaturated 0.012 0.082 3′-cyclopropyl-4′-Pyridyl o-Fluorophenyln-propyl 29 CONH₂ unsaturated 0.036 0.293 3′-cyclopropyl-4′-Pyridylo-Fluorophenyl n-propyl 30 H unsaturated 0.328 0.310 4′-Pyridyl PhenylMethyl 31 CN saturated 0.476 0.643 4′-Pyridyl Phenyl Methyl 32 CONH₂saturated >2 5.39 4′-Pyridyl Phenyl Methyl 33 CN saturated 0.154 1.243′-cyclopropyl-4′-Pyridyl o-Fluorophenyl n-propyl

The relationship between biological activity and the A-ring Michaelacceptor is consistent with a covalent drug:protein interaction, mostlikely involving one of the 8 free cysteines in the RORγ/RORγt LBD.While this mechanism of action (MOA) has been exploited successfullyagainst other protein classes, most notably with kinases, it is rare inthe nuclear receptor (NR) field, especially in the ROR family of NRs.The chemical biology literature of NRs provides few insights on how toidentify the specific cysteine in the LBD of RORγ/RORγt central to theinverse agonism observed. PPARγ was the lone exception, where severalendogenous fatty acid metabolite ligands (e.g. PGJ₂), have been shown tobind in the orthosteric site, ligate Cysteine 285 on alpha helix H3, andregulate the NR's transcriptional activity. Interestingly, Cysteine 320on alpha helix H3 of RORγt occupies precisely the same location relativeto the RORγt orthosteric site, as Cysteine 285 does on PPARγ. With thisin mind, full-length human RORγt constructs were generated whereCysteine 320 (Cysteine 299 in RORγt) was mutated to Alanine as well asSerine, and the activity of compounds 14 and 21 in full-length RORγtRORE-luciferase reporter assays in Jurkat cells was assessed using thesemutants. Compounds 14 and 21 were found to be refractory to bothmutations, displaying similar activity against the wild-type and mutantRORγt proteins (Table 4). Supportive of these results, compounds 14 and21 were found not to compete with cholesterol sulfate, a knownorthosteric RORγt ligand, in competitive binding experiments using theRORγt LBD.

TABLE 4 Effect of Cysteine Mutations in Human RORγ on InhibitoryActivity of Selected Compounds RORγt IC₅₀ (nM) RORγ (RORγt)^(a) Compound14 Compound 21 Wild Type 35.7 +/− 13.1 39.5 +/− 9.5  C320S (C299S) 36.7+/− 13.4 58.3 +/− 20.9 C320A (C299A) 43.7 +/− 11.8 64.1 +/− 24.0 C476S(C455S) ND ND C476A (C455A) ND ND C393S (C372S) 60.4 +/− 25.2 48.7 +/−20.0 C285S (C264S) 37.6 +/− 17.2 28.1 +/− 9.7  C455S (C434S) 37.5 +/−17.9 52.6 +/− 18.5 C278S (C257S) 41.3 +/− 14.9 46.5 +/− 13.8 C366S(C345S) 39.0 +/− 7.6  50.3 +/− 12.3 C345S (C324S) 33.9 +/− 14.8 37.4 +/−11.3 ND—IC₅₀ value could not be determined because RORγt was notinhibited at concentrations that did not affect cellular viability^(a)Residue numbering is according to full-length human RORγ with humanRORγt numbering shown in brackets

Next, expression plasmids serially mutating the seven remaining freecysteine residues on RORγ to serine and/or alanine were generated. Insubsequent reporter gene assays, only mutation of Cysteine 476 affectedthe ability of compounds 14 and 21 to inhibit RORγ (Table 4). Inaddition, the binding of compound 21 to Cysteine 476 was confirmed byhydrogen/deuterium exchange (HDX) mass spectrometry (MS).

Cysteine 476 resides on alpha helix H11 of RORγ and coincidentally is onthe periphery of the allosteric site previously described by Merck andEindhoven. In binding experiments, compound 21 and MRL-871, a knownallosteric modulator of RORγ, were found to be mutually competitive.Moreover, no complex was observed in which MRL-871 and compound 21 weresimultaneously bound to RORγt. However, the binding of MRL-871 was notaffected by the presence of the C476S mutation. In addition, MRL-871displayed similar activity against the wild-type and C476S mutant RORγtprotein. Taken together these data support a MOA where compound 12 bindsto an allosteric site through a specific covalent interaction withCysteine 476, thereby inhibiting the transcriptional activity ofRORγ/RORγt.

Cysteine 476 is strictly conserved among all three ROR isoforms: alpha,beta, and gamma. Nonetheless, it is rarely found in the remaining 45human NRs, occurring only in the orphan receptors nerve growth factor1B(NGF1B), testicular receptor2 (NR2C2), and nuclear receptor related1(NR4A2) receptors. The inhibitory activity of compound 14 was evaluatedagainst a panel of seventeen human NRs from the NR1 subfamily and foundno appreciable activity at concentrations that did not affect cellviability. Furthermore, compounds 14 and 21 showed good ROR isoformselectivity, inhibiting RORγ/RORγt activity without measurable effectson RORα or RORβ activity at concentrations that did not affect cellviability (see FIGS. 1A-1B for data using compound 14).

Towards the goal of developing a predictive model consistent with theobserved potency, selectivity and MOA of this drug class, moleculardynamics (MD) simulations were utilized. A covalent docking protocol wasdeveloped within MOE and applied to compound 21 using the MRL-871/RORγtprotein crystal structure.

The biological activity of compound 14 was further characterized byassessing its ability to inhibit Th17 differentiation of human naïveCD4+ T cells cultured in vitro under Th17-polarizing conditions.Compound 14 potently inhibited Th17 differentiation, as measured by thepercentage of IL-17A-expressing cells, with an average IC₅₀ value of 30nM (FIG. 2A). Compound 14 also significantly reduced the expression ofkey Th17 signature genes, including IL17A, IL17F, and CCL20 (FIGS.2B-6D). Under the Th17 differentiating protocol used for theseexperiments, compound 14 reduced cell viability by 10-15% at the highestconcentration (FIG. 2A).

Compound 14 was evaluated for oral bioavailability, and consistent withits physicochemical properties, compound 14 easily achieves therapeuticsystemic exposures after a single oral dosing to mice. Compound 14 wasthen evaluated for pharmacological activity in the collagen-inducedrheumatoid arthritis (CIA) mouse model, as RORγt has been shown to beimportant in the pathophysiology of this model (Park, 2014) and inpatients with rheumatoid arthritis (Paradowska-Gorycka, 2016). The studywas conducted and progression of disease severity evaluated aspreviously described (Scales, 2016). Compound 14 significantly decreasedboth the clinical scores and paw thickness measurements, starting asearly as one week after starting treatment and continuing untiltermination of the study on Day 42 (FIGS. 3A-3B). Collectively, thesedata provide in vivo proof of concept for this series of compounds.

Example 2: Compound Synthesis and Characterization General Information

Unless otherwise stated, commercially reagents were used as received,and all reactions were run under nitrogen atmosphere. All solvents wereof HPLC or ACS grade. Nuclear magnetic resonance (NMR) spectra wererecorded on a Varian Inova-400 spectrometer at operating frequencies of400 MHz (¹H NMR). Chemical shifts (δ) are given in ppm relative toresidual solvent (usually chloroform δ 7.26 ppm for ¹H NMR), andcoupling constants (J) in Hz. Multiplicity is tabulated as s forsinglet, d for doublet, t for triplet, q for quadruplet, and m formultiplet. Mass spectra were recorded on Agilent 6120 mass spectrometer.

Compound I-2: To a solution of compound I-1 (20 g, 71.87 mmol) in EtOH(200 mL) was added 10% wet Pd/C (2 g). The mixture was stirred at 20° C.for 16 h under hydrogen (15 Psi) and filtered. The filtrate wasconcentrated to give compound I-2 (15.8 g, 78% yield) as a colorlessoil. m/z=267 (M+1).

Compound I-3: To a solution of compound I-2 (5.022 g, 18.85 mmol) inEtOH (50 mL) was added NaBH₄ (357 mg, 9.38 mmol) at 0° C. in 1 portion.After the mixture was stirred at 0° C. for 3 h, additional amount ofNaBH₄ (100 mg, 2.62 mmol) was added. The mixture was stirred at ambienttemperature for 30 min. TLC indicated the starting material wascompletely consumed. The mixture was cooled to 0° C. 3 N aq. HCl (80 mL,240 mmol) was added. The mixture was stirred at room temperature for 20h and concentrated. The residue was extracted with EtOAc (2×30 mL). Thecombined organic extracts were dried with Na₂SO₄, filtered, andconcentrated. The residue was purified by column chromatography (silicagel, eluting with 0% to 40% EtOAc in hexanes) to give compound I-3(3.850 g, 91% yield) as viscous oil. Compound I-3 is 1.6/1 mixture ofdiastereomers (determined by ¹H NMR).

Compound I-4 and I-5: To a solution of compound I-3 (1.011 g, 4.51 mmol)in EtOH (15 mL) were added 2-fluorobenzaldehyde (697 mg, 5.62 mmol) andpotassium fluoride on alumina (5.5 mmol/g, 1.23 g, 6.765 mmol)sequentially at room temperature. The mixture was stirred at roomtemperature under N₂ for 20 h, diluted with EtOAc (30 mL), and filteredthrough a pad of Celite®. The filter cake was washed with EtOAc. Thefiltrate was concentrated, and the residue was partitioned between EtOAc(50 mL) and water (20 mL). The aqueous phase was extracted with EtOAc(30 mL). The combined organic extracts were dried with Na₂SO₄ andconcentrated. The residue was purified by column chromatography (silicagel, eluting with 0 to 40% EtOAc in hexanes) to give compound I-4 (459mg, 31% yield) and compound I-5 (743 mg, 50% yield) as white solids.Compound I-4: m/z=331 (M+1); Compound I-5: m/z=331 (M+1).

Compound I-7a: A mixture of compound I-4 (152 mg, 0.46 mmol), compoundI-6a (156 mg, 0.69 mmol) and K₂CO₃ (191 mg, 1.38 mmol) in EtOH (4 mL)was heated in a sealed vial at 100° C. for 48 h. After cooled to roomtemperature, the mixture was diluted with EtOAc (20 mL) and washed withwater (3×15 mL) and brine (15 mL). The organic extract was dried withNa₂SO₄, filtered, and concentrated. The crude product was dissolved inCH₂Cl₂ (4 mL), and treated with MnO₂ (88%, 0.36 g, 3.65 mmol) at roomtemperature. The mixture was stirred at room temperature for 20 h andpurified by column chromatography (silica gel, eluting with 0-50% EtOAcin hexanes) to give compound I-7a (103 mg, 45% yield) as a light yellowsolid. m/z=500 (M+1).

Compound I-7b: Following the same procedure as described for thesynthesis of compound I-7a, compound I-7b (light yellow solid; 119 mg,56% yield) was synthesized from compound I-4 (152 mg, 0.46 mmol) andcompound I-6b (131 mg, 0.69 mmol). m/z=464 (M+1).

Compound I-8a: Compound I-7a (96.0 mg, 0.19 mmol) and Dess-Martinperiodinane (163 mg, 0.38 mmol) in CH₂Cl₂ (2 mL) was stirred at roomtemperature for 3 h. The mixture was treated with 10% aq. Na₂SO₃ (5 mL)and sat. aq. NaHCO₃ (5 mL), stirred at room temperature for 10 min, andextracted with t-butyl methyl ether (2×15 mL). The combined organicextracts were washed with sat. aq. NaHCO₃, dried with Na₂SO₄, filtered,and concentrated. The residue was purified by column chromatography(silica gel, eluting with 0-35% EtOAc in hexanes) to give compound I-8a(87 mg, 91% yield) as a white solid. m/z=498 (M+1).

Compound I-8b: Following the same procedure as described for thesynthesis of compound I-8a, compound I-8b (white solid; 105 mg, 92%yield) was synthesized from compound I-7b (115 mg, 0.25 mmol). m/z=462(M+1).

Compound I-9a: To a mixture of compound I-8a (85 mg, 0.17 mmol) in ethylformate (0.42 mL, 5.1 mmol) at 0° C. under N₂ was added sodium methoxide(4.37 M in MeOH, 0.39 mL, 1.7 mmol). The mixture was stirred at ambienttemperature for 2 h and then cooled to 0° C. 6 N aq. HCl (0.28 mL, 1.7mmol), EtOH (1.7 mL), and hydroxylamine hydrochloride (22 mg, 0.32 mmol)were added sequentially. The mixture was heated at 55° C. for 16 h, andthen cooled to room temperature. The mixture was diluted with sat. aq.NaHCO₃ (5 mL) and extracted with EtOAc (20 mL). The organic extract waswashed with water (10 mL), dried with Na₂SO₄, filtered, andconcentrated. The residue was purified by column chromatography (silicagel, eluting with 0 to 40% EtOAc in hexanes) to give compound I-9a (66mg, 74% yield) as a light yellow solid. m/z=523 (M+1).

Compound I-9b: Following the same procedure as described for thesynthesis of compound I-9a, compound I-9b (white solid; 91 mg, 84%yield) was synthesized from compound I-8b (103 mg, 0.22 mmol). m/z=487(M+1).

Compound I-10a: To a solution of compound I-9a (63 mg, 0.12 mmol) inMeOH (1.2 mL) at room temperature under N₂ was added sodium methoxide(4.37 M, 55 μL, 0.24 mmol). The mixture was stirred at 55° C. for 1.5 h,cooled to room temperature, treated with 10% aq. NaH₂PO₄ (5 mL), andextracted with EtOAc (30 mL). The organic extract was washed with water(10 mL), dried with MgSO₄, filtered, and concentrated. The residue waspurified by column chromatography (silica gel, eluting with 0 to 50%EtOAc in hexanes) to give compound I-10a (52 mg, 83% yield) as a whitesolid. m/z=523 (M+1).

Compound I-10b: Following the same procedure as described for thesynthesis of compound I-10a, compound I-10b (white solid; 77 mg, 89%yield) was synthesized from compound I-9b (87 mg, 0.18 mmol). m/z=487(M+1).

Compound 22: Compound I-10a (52 mg, 0.10 mmol) in DMF (0.36 mL) wascooled to 0° C. under N₂. 1,3-dibromo-5,5-dimethylhydantoin (14 mg,0.050 mmol) in DMF (0.14 mL) was added. The solution was stirred at 0°C. for 1 h. Pyridine (24 μL, 0.30 mmol) was added. The mixture washeated at 55° C. for 4 h, cooled to room temperature, diluted with EtOAc(20 mL), and washed with water (3×15 mL). The organic extract was driedwith Na₂SO₄, filtered, and concentrated. The residue was purified bycolumn chromatography (silica gel, eluting 0 to 50% EtOAc in hexanes) togive compound 22 (47 mg, 91% yield) as an off-white solid. m/z=521(M+1); ¹H NMR (400 MHz, CDCl₃) δ 8.94 (s, 1H), 8.91 (d, J=5.0 Hz, 1H),8.70 (dd, J=1.5, 0.8 Hz, 1H), 8.57 (dd, J=5.1, 1.5 Hz, 1H), 7.54 (m,1H), 7.45 (td, J=7.4, 1.8 Hz, 1H), 7.35 (td, J=7.5, 1.1 Hz, 1H), 7.23(m, 1H), 2.93-2.77 (m, 2H), 2.61 (ddd, J=13.1, 5.0, 3.2 Hz, 1H), 2.46(td, J=12.8, 2.5 Hz, 1H), 2.14-2.06 (m, 2H), 1.81 (m, 1H), 1.69 (m, 1H),1.55 (s, 3H), 1.35 (m, 1H), 1.22 (m, 1H), 0.93 (t, J=7.3 Hz, 3H).

Compound 23: Following the same procedure as described for the synthesisof compound 22, compound 23 (off-white solid; 68 mg, 89% yield) wassynthesized from compound I-10b (77 mg, 0.16 mmol). m/z=485 (M+1); ¹HNMR (400 MHz, CDCl₃) δ 8.98 (s, 1H), 8.76 (d, J=5.2 Hz, 1H), 8.48 (s,1H), 8.31 (ddd, J=5.1, 1.7, 0.8 Hz, 1H), 7.52 (m, 1H), 7.45 (td, J=7.4,1.8 Hz, 1H), 7.34 (td, J=7.5, 1.1 Hz, 1H), 7.22 (ddd, J=9.7, 8.5, 1.1Hz, 1H), 5.60 (d, J=46.9 Hz, 2H), 2.93-2.73 (m, 2H), 2.60 (ddd, J=13.1,5.0, 3.2 Hz, 1H), 2.46 (td, J=12.8, 2.5 Hz, 1H), 2.15-2.05 (m, 2H), 1.82(m, 1H), 1.69 (m, 1H), 1.54 (s, 3H), 1.34 (m, 1H), 1.19 (m, 1H), 0.93(t, J=7.2 Hz, 3H).

Compound 29: A mixture of compound 21 (70 mg, 0.14 mmol) andhydrido(dimethylphosphinous acid-kP)[hydrogenbis(dimethylphosphinito-kP)]platinum(II) (6.1 mg, 14 μmol) in EtOH (1mL) and water (1 mL) were heated at 90° C. for 4 h open to the air.After cooled to room temperature, the mixture was concentrated. Theresidue was extracted with EtOAc (2×15 mL). The organic extract wasdried with Na₂SO₄, filtered, and concentrated. The residue was purifiedby column chromatography (silica gel, eluting with 0 to 100% EtOAc inhexanes) to give impure product, which was purified again by columnchromatography (silica gel, eluting with 0 to 50% acetone in hexanes) togive compound 29 (33 mg, 45% yield) as a white solid. m/z=511 (M+1); ¹HNMR (400 MHz, CDCl₃) δ 9.47 (s, 1H), 8.58 (d, J=5.1 Hz, 1H), 8.50 (d,J=5.1 Hz, 1H), 8.24 (s, 1H), 8.13 (dd, J=5.1, 1.6 Hz, 1H), 7.53-7.42 (m,2H), 7.32 (t, J=7.5 Hz, 1H), 7.20 (t, J=9.1 Hz, 1H), 5.68 (d, J=4.5 Hz,1H), 2.89-2.70 (m, 2H), 2.62 (ddd, J=12.9, 5.2, 3.4 Hz, 1H), 2.42 (td,J=12.8, 2.5 Hz, 1H), 2.19 (m, 1H), 2.14-1.99 (m, 2H), 1.91-1.63 (m, 2H),1.50 (s, 3H), 1.43-1.13 (m, 2H), 1.10 (m, 2H), 1.02 (m, 2H), 0.93 (t,J=7.3 Hz, 3H).

Compound 30: A solution of compound I-11 (225 mg, 0.59 mmol) and2-iodoxybenzoic acid (657 mg, 2.35 mmol) in DMSO (5 mL) was heated at80-85° C. under nitrogen for 20 h. The reaction mixture was cooled toroom temperature and diluted with t-butyl methyl ether (50 mL). Themixture was stirred for 10 min and filtered through a pad of Celite®.The filter cake was washed with t-butyl methyl ether (2×25 mL). Thefiltrate was washed with water (3×50 mL). The organic extract was driedwith Na₂SO₄, filtered, and concentrated. The residue was purified bycolumn chromatography (silica gel, eluting with 0 to 70% EtOAc inhexanes) to give a mixture of compound I-11 and compound 30 (150 mg).

The mixture of compound I-11 and compound 30 (72 mg, 0.19 mmol) inethylene glycol (1 mL) was treated with p-toluenesulfonic acidmonohydrate (35.7 mg, 0.19 mmol) at at room temperature. The mixture wasstirred at room temperature for 30 min, compound I-11 was converted tocompound I-12. The mixture was diluted with CH₂Cl₂ (20 mL), poured intosat. aq. NaHCO₃ (20 mL), and stirred for 5 min. The organic layer wasseparated. The aqueous layer was extracted with CH₂Cl₂ (20 mL). Thecombined organic extracts were dried with Na₂SO₄, filtered, andconcentrated. The residue was purified by column chromatography (silicagel, eluting with 0 to 50% acetone in hexanes) to give compound 30 (32mg, 30% yield from I-11) as a white solid. m/z=382 (M+1); ¹H NMR (400MHz, CDCl₃) δ 8.76 (m, 2H), 8.38 (m, 2H), 8.28 (d, J=10.1 Hz, 1H),7.63-7.58 (m, 2H), 7.55-7.49 (m, 3H), 6.12 (d, J=10.1 Hz, 1H), 3.06-2.89(m, 2H), 2.53 (dq, J=13.5, 6.8 Hz, 1H), 2.21 (td, J=12.7, 2.7 Hz, 1H),2.11 (m, 1H), 1.75 (m, 1H), 1.47 (s, 3H), 1.27 (d, J=6.7 Hz, 3H).

Compound 32: A mixture of compound I-13 (35 mg, 0.086 mmol) andhydrido(dimethylphosphinous acid-kP)[hydrogenbis(dimethylphosphinito-kP)]platinum(II) (3.5 mg, 8.6 μmmol) in EtOH (1mL) and water (1 mL) were heated at 90° C. for 4 h open to the air.After cooled to room temperature, the mixture was concentrated. Theresidue was extracted with EtOAc. The organic extract was dried withNa₂SO₄, filtered, and concentrated. The residue was purified by columnchromatography (silica gel, eluting 0 to 100% EtOAc in hexanes) to giveimpure product, which was purified again by column chromatography(silica gel, eluting 0 to 50% acetone in hexanes) to give compound 32(mixture of tautomers, 8 mg, 22% yield) as a white solid. m/z=427 (M+1);¹H NMR (400 MHz, CDCl₃) δ major tautomer: 8.73 (m, 2H), 8.32 (m, 2H),7.65-7.59 (m, 2H), 7.54-7.48 (m, 3H), 4.78 (bs, 2H), 3.06 (d, J=14.5 Hz,1H), 2.99-2.80 (m, 2H), 2.39 (dd, J=14.6, 2.6 Hz, 1H), 2.29 (m, 1H),2.05 (m, 1H), 1.69 (ddd, J=12.9, 11.0, 2.3 Hz, 1H), 1.50 (m, 1H), 1.32(d, J=6.8 Hz, 3H), 1.28 (s, 3H).

All of the compounds, compositions, and methods disclosed and claimedherein can be made and executed without undue experimentation in lightof the present disclosure. While the disclosure may have focused onseveral embodiments or may have been described in terms of preferredembodiments, it will be apparent to those of skill in the art thatvariations and modifications may be applied to the compounds,compositions, and methods without departing from the spirit, scope, andconcept of the invention. All variations and modifications apparent tothose skilled in the art are deemed to be within the spirit, scope, andconcept of the invention as defined by the appended claims.

REFERENCES

The following references to the extent that they provide exemplaryprocedural or other details supplementary to those set forth herein, arespecifically incorporated herein by reference.

-   PCT/US2013/045975 (WO 2013/188818)-   PCT/US2017/000094 (WO 2018/111315)-   PCT/US2019/037543-   Anderson, Practical Process Research & Development—A Guide for    Organic Chemists, 2^(nd) ed., Academic Press, New York, 2012.-   Bronner, et al., Expert Opin. Ther. Pat., 1:101-112, 2017.-   Coltart and Danishefsky, Org. Lett., 5:1289, 2003.-   Fujiwara, et al., J. Immunol., 193(5):2565-73, 2014.-   Handbook of Pharmaceutical Salts: Properties, and Use, Stahl and    Wermuth Eds., Verlag Helvetica Chimica Acta, 2002.-   Lu et al., J. Clin. Invest., 121(10):4015-29, 2011.-   Miosse and Kolls, Nature Reviews, 11(10):763-776, 2012.-   Reagan-Shaw et al., FASEB J., 22(3):659-661, 2008.-   Smith, March's Advanced Organic Chemistry: Reactions, Mechanisms,    and Structure, 7^(th) Ed., Wiley, 2013.-   Waite and Skokos, International Journal of Inflammation, 2012:1-10,    2011.

What is claimed is:
 1. A method of treating a disease or disorder in apatient in need thereof, comprising administering to the patient atherapeutically effective amount of a cysteine-dependent inverse agonistof the nuclear receptor RORγ/RORγt.
 2. The method of claim 1, whereinthe therapeutically effective amount is sufficient to modulate theactivity of the nuclear receptor RORγ/RORγt in the patient.
 3. Themethod of claim 1, wherein the inverse agonist binds to cysteine 476 ofthe nuclear receptor RORγ (see SEQ ID NO: 1) in the patient.
 4. Themethod of claim 3, wherein the binding occurs via the formation of acovalent bond between the inverse agonist and the cysteine
 476. 5. Themethod of claim 3, wherein the inverse agonist selectively binds tocysteine 476 of the nuclear receptor RORγ in the patient.
 6. The methodof claim 3, wherein the inverse agonist preferentially binds to cysteine476 of the nuclear receptor RORγ relative to the orthosteric bindingpocket in the ligand binding domain (LBD) of RORγ/RORγt in the patient.7. The method of claim 1, wherein the inverse agonist does not bind toany significant extent to the orthosteric binding pocket in the ligandbinding domain (LBD) of RORγ/RORγt in the patient.
 8. The method ofclaim 1, wherein the inverse agonist inhibits activity of the nuclearreceptor RORγ/RORγt without significantly affecting activity of thenuclear receptor RORα or the nuclear receptor RORβ in the patient. 9.The method according to any one of claims 1-8, wherein the methodmodulates the function of the nuclear receptor RORγ in the patient. 10.The method according to any one of claims 1-8, wherein the methodsuppresses interleukin-17A production in the patient.
 11. The methodaccording to any one of claims 1-8, wherein the method selectivelyinhibits T helper 17 (Th17) cell differentiation in the patient.
 12. Themethod according to any one of claims 1-8, wherein the inverse agonist'sRORγt-LBD-GAL4 reporter assay IC₅₀ activity is less than 1 μM.
 13. Themethod of claim 12, wherein the inverse agonist's RORγt-LBD-GAL4reporter assay IC₅₀ activity is less than 500 nM.
 14. The method ofclaim 13, wherein the inverse agonist's RORγt-LBD-GAL4 reporter assayIC₅₀ activity is less than 100 nM.
 15. The method according to any oneof claims 1-8, wherein the inverse agonist's suppression of IL-17Asecretion from human CD4+ T-cells assay IC₅₀ activity is less than 500nM.
 16. The method of claim 15, wherein the inverse agonist'ssuppression of IL-17A secretion from human CD4+ T-cells assay IC₅₀activity is less than 100 nM.
 17. The method of claim 16, wherein theinverse agonist's suppression of IL-17A secretion from human CD4+T-cells assay IC₅₀ activity is less than 50 nM.
 18. The method accordingto any one of claims 1-17, wherein the disease or disorder is anautoimmune disease.
 19. The method of claim 18, wherein the autoimmunedisease is Crohn's disease, rheumatoid arthritis, lupus, or psoriasis.20. The method of claim 18, wherein the autoimmune disease is rheumatoidarthritis.
 21. The method of claim 18, wherein the autoimmune disease ispsoriasis.
 22. The method according to any one of claims 1-21, whereinthe chemical formula of the inverse agonist comprises a chemical groupof the formula:

wherein: the bond between carbon atoms 1 and 2 is an epoxidized doublebond or a double bond; the bond between carbon atoms 4 and 5 is a singlebond or a double bond; R₁ is cyano, heteroaryl_((C≤8)), substitutedheteroaryl_((C≤8)), —CF₃, or —C(O)R_(a); wherein: R_(a) is hydroxy,amino, or alkoxy_((C≤8)), alkylamino_((C≤8)), dialkylamino_((C≤8)),alkylsulfonylamino_((C≤8)), or a substituted version of any of thesegroups; R₂ is hydrogen or alkyl_((C≤12)), cycloalkyl_((C≤12)),alkenyl_((C≤12)), alkynyl_((C≤12)), aryl_((C≤12)), aralkyl_((C≤12)),heteroaryl_((C≤12)), heteroaralkyl_((C≤12)), acyl_((C≤12)), or asubstituted version of any of these groups, or-alkanediyl_((C≤8))-cycloalkyl_((C≤12)) or a substituted version of thisgroup; R_(2′) is absent, hydrogen, or alkyl_((C≤12)),cycloalkyl_((C≤12)), alkenyl_((C≤12)), alkynyl_((C≤12)), aryl_((C≤12)),aralkyl_((C≤12)), heteroaryl_((C≤12)), heteroaralkyl_((C≤12)),acyl_((C≤12)), or a substituted version of these groups; provided thatwhen the bond between carbon atoms 4 and 5 is a double bond then R_(2′)is absent; and R₃ is alkyl_((C≤12)), alkenyl_((C≤12)), aryl_((C≤12)),aralkyl_((C≤12)), or a substituted version of any of these groups. 23.The method of claim 22, wherein the formula is further defined as:

wherein: R₁ is cyano, heteroaryl_((C≤8)), substitutedheteroaryl_((C≤8)), —CF₃, or —C(O)R_(a); wherein: R_(a) is hydroxy,amino, or alkoxy_((C≤8)), alkylamino_((C≤8)), dialkylamino_((C≤8)),alkylsulfonylamino_((C≤8)), or a substituted version of any of thesegroups; R₂ is hydrogen or alkyl_((C≤12)), cycloalkyl_((C≤12)),alkenyl_((C≤12)), alkynyl_((C≤12)), aryl_((C≤12)), aralkyl_((C≤12)),heteroaryl_((C≤12)), heteroaralkyl_((C≤12)), acyl_((C≤12)), or asubstituted version of any of these groups, or-alkanediyl_((C≤8))-cycloalkyl_((C≤12)) or a substituted version of thisgroup; R_(2′) is absent, hydrogen, or alkyl_((C≤12)),cycloalkyl_((C≤12)), alkenyl_((C≤12)), alkynyl_((C≤12)), aryl_((C≤12)),aralkyl_((C≤12)), heteroaryl_((C≤12)), heteroaralkyl_((C≤12)),acyl_((C≤12)), or a substituted version of these groups; provided thatwhen the bond between carbon atoms 4 and 5 is a double bond then R_(2′)is absent; and R₃ is alkyl_((C≤12)), alkenyl_((C≤12)), aryl_((C≤12)),aralkyl_((C≤12)), or a substituted version of any of these groups. 24.The method of either claim 22 or claim 23, wherein the formula isfurther defined as:

wherein: R₂ is hydrogen or alkyl_((C≤12)), cycloalkyl_((C≤12)),alkenyl_((C≤12)), alkynyl_((C≤12)), aryl_((C≤12)), aralkyl_((C≤12)),heteroaryl_((C≤12)), heteroaralkyl_((C≤12)), acyl_((C≤12)), or asubstituted version of any of these groups, or-alkanediyl_((C≤8))-cycloalkyl_((C≤12)) or a substituted version of thisgroup; R_(2′) is absent, hydrogen, or alkyl_((C≤12)),cycloalkyl_((C≤12)), alkenyl_((C≤12)), alkynyl_((C≤12)), aryl_((C≤12)),aralkyl_((C≤12)), heteroaryl_((C≤12)), heteroaralkyl_((C≤12)),acyl_((C≤12)), or a substituted version of these groups; provided thatwhen the bond between carbon atoms 4 and 5 is a double bond then R_(2′)is absent; and R₃ is alkyl_((C≤12)), alkenyl_((C≤12)), aryl_((C≤12)),aralkyl_((C≤12)), or a substituted version of any of these groups. 25.The method according to any one of claims 22-24, wherein the formula isfurther defined as:

wherein: R₂ is hydrogen or alkyl_((C≤12)), cycloalkyl_((C≤12)),alkenyl_((C≤12)), alkynyl_((C≤12)), aryl_((C≤12)), aralkyl_((C≤12)),heteroaryl_((C≤12)), heteroaralkyl_((C≤12)), acyl_((C≤12)), or asubstituted version of any of these groups, or-alkanediyl_((C≤8))-cycloalkyl_((C≤12)) or a substituted version of thisgroup.
 26. The method according to any one of claims 22-25, wherein theformula is further defined as:


27. The method according to any one of claims 1-22, wherein the inverseagonist is a compound of the formula:

wherein: the bond between carbon atoms 1 and 2 is an epoxidized doublebond or a double bond; the bond between carbon atoms 4 and 5 is a singlebond or a double bond; a is 0, 1, or 2; R₁ is cyano, heteroaryl_((C≤8)),substituted heteroaryl_((C≤8)), —CF₃, or —C(O)R_(a); wherein: R_(a) ishydroxy, amino, or alkoxy_((C≤8)), alkylamino_((C≤8)),dialkylamino_((C≤8)), alkylsulfonylamino_((C≤8)), or a substitutedversion of any of these groups; R₂ is hydrogen or alkyl_((C≤12)),cycloalkyl_((C≤12)), alkenyl_((C≤12)), alkynyl_((C≤12)), aryl_((C≤12)),aralkyl_((C≤12)), heteroaryl_((C≤12)), heteroaralkyl_((C≤12)),acyl_((C≤12)), or a substituted version of any of these groups, or-alkanediyl_((C≤8))-cycloalkyl_((C≤12)) or a substituted version of thisgroup; R_(2′) is absent, hydrogen, or alkyl_((C≤12)),cycloalkyl_((C≤12)), alkenyl_((C≤12)), alkynyl_((C≤12)), aryl_((C≤12)),aralkyl_((C≤12)), heteroaryl_((C≤12)), heteroaralkyl_((C≤12)),acyl_((C≤12)), or a substituted version of these groups; provided thatwhen the bond between carbon atoms 4 and 5 is a double bond then R_(2′)is absent; R₃ is alkyl_((C≤12)), alkenyl_((C≤12)), aryl_((C≤12)),aralkyl_((C≤12)), or a substituted version of any of these groups; R₄ ishydrogen, amino, alkyl_((C≤18)), substituted alkyl_((C≤18)),cycloalkyl_((C≤18)), substituted cycloalkyl_((C≤18)), aryl_((C≤18)),substituted aryl_((C≤18)), aralkyl_((C≤18)), substitutedaralkyl_((C≤18)), heteroaryl_((C≤18)), substituted heteroaryl_((C≤18)),heteroaralkyl_((C≤18)), substituted heteroaralkyl_((C≤18)),heterocycloalkyl_((C≤18)), substituted heterocycloalkyl_((C≤18)),amido_((C≤18)), substituted amido_((C≤18)), or—X₁—(CH₂)_(m)—R_(4′); wherein: X₁ is NR_(b), O, or S; wherein: R_(b) ishydrogen, alkyl_((C≤6)), or substituted alkyl_((C≤6)); m is 0, 1, 2, 3,or 4; and R_(4′) is alkyl_((C≤12)), cycloalkyl_((C≤12)), aryl_((C≤18)),aralkyl_((C≤18)), heteroaryl_((C≤18)), heteroaralkyl_((C≤18)),heterocycloalkyl_((C≤18)), or a substituted version of any of thesegroups; or

wherein: n is 0, 1, 2, 3, or 4; and R_(4″) is —H, —OH, —F, —Cl, —Br, —I,—NH₂, —NO₂, —CN, —SH, —S(O)₂OH, or —S(O)₂NH₂, or alkyl_((C≤8)),cycloalkyl_((C≤8)), aryl_((C≤8)), heteroaryl_((C≤8)),heterocycloalkyl_((C≤8)), acyl_((C≤8)), amido_((C≤8)), alkoxy_((C≤8)),acyloxy_((C≤8)), alkylamino_((C≤8)), dialkylamino_((C≤8)),—C(O)-alkoxy_((C≤8)), —C(O)-alkylamino_((C≤8)),—C(O)-dialkyl-amino_((C≤8)), alkylsulfonyl_((C≤8)),arylsulfonyl_((C≤8)), alkoxysulfonyl_((C≤8)), or a substituted versionof any of these groups; or—X₂—(CH₂)_(p)—R_(4′″); wherein: X₂ is arenediyl_((C≤12)), substitutedarenediyl_((C≤12)), heterocycloalkanediyl_((C≤12)), substitutedheterocycloalkanediyl_((C≤12)), heteroarenediyl_((C≤12)), or substitutedheteroarenediyl_((C≤12)); p is 0, 1, 2, 3, or 4; and R_(4′″) isalkyl_((C≤8)), cycloalkyl_((C≤8)), aryl_((C≤8)), heteroaryl_((C≤8)),heterocycloalkyl_((C≤8)), acyl_((C≤8)), amido_((C≤8)), alkoxy_((C≤8)),acyloxy_((C≤8)), —C(O)-alkoxy_((C≤8)), —C(O)-alkylamino_((C≤8)),—C(O)-dialkyl-amino_((C≤8)), alkylsulfonyl_((C≤8)),arylsulfonyl_((C≤8)), alkoxysulfonyl_((C≤8)), or a substituted versionof any of these groups; and R₅ is amino, hydroxy, —OS(O)₂C₆H₄CH₃,alkyl_((C≤12)), alkoxy_((C≤12)), cycloalkyl_((C≤12)),cycloalkoxy_((C≤12)), aryl_((C≤12)), aralkyl_((C≤12)),heteroaryl_((C≤12)), heteroaralkyl_((C≤12)), heterocycloalkyl_((C≤12)),acyl_((C≤12)), acyloxy_((C≤12)), alkylamino_((C≤12)),dialkylamino_((C≤12)), alkylsulfonylamino_((C≤12)), or a substitutedversion of any of the last fourteen groups, or—OY₁-A₁; wherein: Y₁ is alkanediyl_((C≤8)) or substitutedalkanediyl_((C≤8)); and A₁ is cycloalkyl_((C≤8)) or substitutedcycloalkyl_((C≤8)); or—Y₂—C(O)NR_(c)-A₂; wherein: Y₂ is arenediyl_((C≤8)) or substitutedarenediyl_((C≤8)); R_(c) is hydrogen, alkyl_((C≤6)), or substitutedalkyl_((C≤6)); and A₂ is aralkyl_((C≤12)) or substitutedaralkyl_((C≤12)); or-A₃R_(d); wherein: A₃ is —O— or —NR_(e)—, wherein R_(e) is hydrogen,alkyl_((C≤6)), or substituted alkyl_((C≤6)); and R_(d) is acyl_((C≤12)),or substituted acyl_((C≤12)); provided that when carbon atoms 4 and 5are joined by a double bond, then R_(2′) and the hydrogen atom at carbonatom 5 are absent; or a pharmaceutically acceptable salt thereof. 28.The method of claim 27, wherein the compound is further defined as:

wherein: the bond between carbon atoms 1 and 2 is an epoxidized doublebond or a double bond; R₁ is cyano, heteroaryl_((C≤8)), substitutedheteroaryl_((C≤8)), —CF₃, or —C(O)R_(a); wherein: R_(a) is hydroxy,amino, or alkoxy_((C≤8)), alkylamino_((C≤8)), dialkylamino_((C≤8)),alkylsulfonylamino_((C≤8)), or a substituted version of any of thesegroups; R₂ is hydrogen or alkyl_((C≤12)), cycloalkyl_((C≤12)),alkenyl_((C≤12)), alkynyl_((C≤12)), aryl_((C≤12)), aralkyl_((C≤12)),heteroaryl_((C≤12)), heteroaralkyl_((C≤12)), acyl_((C≤12)), or asubstituted version of any of these groups, or-alkanediyl_((C≤8))-cycloalkyl_((C≤12)) or a substituted version of thisgroup; R₃ is alkyl_((C≤12)), aryl_((C≤12)), aralkyl_((C≤12)), or asubstituted version of any of these groups; R₄ is hydrogen, amino,alkyl_((C2-18)), substituted alkyl_((C≤18)), cycloalkyl_((C≤18)),substituted cycloalkyl_((C≤18)), aryl_((C≤18)), substitutedaryl_((C≤18)), aralkyl_((C≤18)), substituted aralkyl_((C≤18)),heteroaryl_((C≤18)), substituted heteroaryl_((C≤18)),heteroaralkyl_((C≤18)), substituted heteroaralkyl_((C≤18)),heterocycloalkyl_((C≤18)), substituted heterocycloalkyl_((C≤18)),alkylamino_((C≤18)), substituted alkylamino_((C≤18)),dialkylamino_((C≤18)), substituted dialkylamino_((C≤18)),alkylthio_((C≤18)), substituted alkylthio_((C≤18)), amido_((C≤18)),substituted amido_((C≤18)), or—X₁—(CH₂)_(m)—R_(4′); wherein: X₁ is NR_(b), O, or S; wherein: R_(b) ishydrogen, alkyl_((C≤6)), or substituted alkyl_((C≤6)); m is 0, 1, 2, 3,or 4; and R_(4′) is alkyl_((C≤12)), cycloalkyl_((C≤18)), aryl_((C≤18)),aralkyl_((C≤18)), heteroaryl_((C≤18)), heteroaralkyl_((C≤18)),heterocycloalkyl_((C≤18)), or a substituted version of any of thesegroups, provided that when X₁ is O, then R_(4′) is not methyl; or

wherein: n is 0, 1, 2, 3, or 4; and R_(4″) is —H, —OH, —F, —Cl, —Br, —I,—NH₂, —NO₂, —CN, —SH, —S(O)₂OH, or —S(O)₂NH₂, or alkyl_((C≤8)),cycloalkyl_((C≤8)), aryl_((C≤8)), heteroaryl_((C≤8)),heterocycloalkyl_((C≤8)), acyl_((C≤8)), amido_((C≤8)), alkoxy_((C≤8)),acyloxy_((C≤8)), alkylamino_((C≤8)), dialkylamino_((C≤8)),—C(O)-alkoxy_((C≤8)), —C(O)-alkylamino_((C≤8)),—C(O)-dialkyl-amino_((C≤8)), alkylsulfonyl_((C≤8)),arylsulfonyl_((C≤8)), alkoxysulfonyl_((C≤8)), or a substituted versionof any of these groups; or—X₂—(CH₂)_(p)—R_(4′″); wherein: X₂ is arenediyl_((C≤12)), substitutedarenediyl_((C≤12)), heterocycloalkanediyl_((C≤12)), substitutedheterocycloalkanediyl_((C≤12)), heteroarenediyl_((C≤12)), or substitutedheteroarenediyl_((C≤12)); p is 0, 1, 2, 3, or 4; and R_(4′″) isalkyl_((C≤8)), cycloalkyl_((C≤8)), aryl_((C≤8)), heteroaryl_((C≤8)),heterocycloalkyl_((C≤8)), acyl_((C≤8)), amido_((C≤8)), alkoxy_((C≤8)),acyloxy_((C≤8)), —C(O)-alkoxy_((C≤8)), —C(O)-alkylamino_((C≤8)),—C(O)-dialkyl-amino_((C≤8)), alkylsulfonyl_((C≤8)),arylsulfonyl_((C≤8)), alkoxysulfonyl_((C≤8)), or a substituted versionof any of these groups; and R₅ is amino, hydroxy, —OS(O)₂C₆H₄CH₃,alkyl_((C≤12)), alkoxy_((C≤12)), cycloalkyl_((C≤12)),cycloalkoxy_((C≤12)), aryl_((C≤12)), aralkyl_((C≤12)),heteroaryl_((C≤12)), heterocycloalkyl_((C≤12)), acyl_((C≤12)),acyloxy_((C≤12)), alkylamino_((C≤12)), dialkylamino_((C≤12)),alkylsulfonylamino_((C≤12)), or a substituted version of any of the lastfourteen groups, or—OY₁-A₁; wherein: Y₁ is alkanediyl_((C≤8)) or substitutedalkanediyl_((C≤8)); and A₁ is cycloalkyl_((C≤8)) or substitutedcycloalkyl_((C≤8)); or—Y₂—C(O)NR_(b)-A₂; wherein: Y₂ is arenediyl_((C≤8)) or substitutedarenediyl_((C≤8)); R_(b) is hydrogen, alkyl_((C≤6)), or substitutedalkyl_((C≤6)); and A₂ is aralkyl_((C≤12)) or substitutedaralkyl_((C≤12)); or-A₃R_(d); wherein: A₃ is —O— or —NR_(e)—, wherein R_(e) is hydrogen,alkyl_((C≤6)), or substituted alkyl_((C≤6)); and R_(d) is acyl_((C≤12)),or substituted acyl_((C≤12)); or a pharmaceutically acceptable saltthereof.
 29. The method of either claim 27 or claim 28, wherein thecompound is further defined as:

wherein: R₁ is cyano, heteroaryl_((C≤8)), substitutedheteroaryl_((C≤8)), —CF₃, or —C(O)R_(a); wherein: R_(a) is hydroxy,amino, or alkoxy_((C≤8)), alkylamino_((C≤8)), dialkylamino_((C≤8)),alkylsulfonylamino_((C≤8)), or a substituted version of any of thesegroups; R₂ is hydrogen or alkyl_((C≤12)), cycloalkyl_((C≤12)),alkenyl_((C≤12)), alkynyl_((C≤12)), aryl_((C≤12)), aralkyl_((C≤12)),heteroaryl_((C≤12)), heteroaralkyl_((C≤12)), acyl_((C≤12)), or asubstituted version of any of these groups, or-alkanediyl_((C≤8))-cycloalkyl_((C≤12)) or a substituted version of thisgroup; R₄ is hydrogen, amino, alkyl_((C2-18)), substitutedalkyl_((C≤18)), cycloalkyl_((C≤18)), substituted cycloalkyl_((C≤18)),aryl_((C≤18)), substituted aryl_((C≤18)), aralkyl_((C≤18)), substitutedaralkyl_((C≤18)), heteroaryl_((C≤18)), substituted heteroaryl_((C≤18)),heteroaralkyl_((C≤18)), substituted heteroaralkyl_((C≤18)),heterocycloalkyl_((C≤18)), substituted heterocycloalkyl_((C≤18)),alkylamino_((C≤18)), substituted alkylamino_((C≤18)),dialkylamino_((C≤18)), substituted dialkylamino_((C≤18)),alkylthio_((C≤18)), substituted alkylthio_((C≤18)), amido_((C≤18)),substituted amido_((C≤18)), or—X₁—(CH₂)_(m)—R_(4′); wherein: X₁ is NR_(b), O, or S; wherein: R_(b) ishydrogen, alkyl_((C≤6)), or substituted alkyl_((C≤6)); m is 0, 1, 2, 3,or 4; and R_(4′) is alkyl_((C≤12)), cycloalkyl_((C≤18)), aryl_((C≤18)),aralkyl_((C≤18)), heteroaryl_((C≤18)), heteroaralkyl_((C≤18)),heterocycloalkyl_((C≤18)), or a substituted version of any of thesegroups, provided that when X₁ is O, then R_(4′) is not methyl; or

wherein: n is 0, 1, 2, 3, or 4; and R_(4″) is —H, —OH, —F, —Cl, —Br, —I,—NH₂, —NO₂, —CN, —SH, —S(O)₂OH, or —S(O)₂NH₂, or alkyl_((C≤8)),cycloalkyl_((C≤8)), aryl_((C≤8)), heteroaryl_((C≤8)),heterocycloalkyl_((C≤8)), acyl_((C≤8)), amido_((C≤8)), alkoxy_((C≤8)),acyloxy_((C≤8)), alkylamino_((C≤8)), dialkylamino_((C≤8)),—C(O)-alkoxy_((C≤8)), —C(O)-alkylamino_((C≤8)),—C(O)-dialkyl-amino_((C≤8)), alkylsulfonyl_((C≤8)),arylsulfonyl_((C≤8)), alkoxysulfonyl_((C≤8)), or a substituted versionof any of these groups; or—X₂—(CH₂)_(p)—R_(4′″); wherein: X₂ is arenediyl_((C≤12)), substitutedarenediyl_((C≤12)), heterocycloalkanediyl_((C≤12)), substitutedheterocycloalkanediyl_((C≤12)), heteroarenediyl_((C≤12)), or substitutedheteroarenediyl_((C≤12)); p is 0, 1, 2, 3, or 4; and R_(4′″) isalkyl_((C≤8)), cycloalkyl_((C≤8)), aryl_((C≤8)), heteroaryl_((C≤8)),heterocycloalkyl_((C≤8)), acyl_((C≤8)), amido_((C≤8)), alkoxy_((C≤8)),acyloxy_((C≤8)), —C(O)-alkoxy_((C≤8)), —C(O)-alkylamino_((C≤8)),—C(O)-dialkyl-amino_((C≤8)), alkylsulfonyl_((C≤8)),arylsulfonyl_((C≤8)), alkoxysulfonyl_((C≤8)), or a substituted versionof any of these groups; and R₅ is amino, hydroxy, —OS(O)₂C₆H₄CH₃,alkyl_((C≤12)), alkoxy_((C≤12)), cycloalkyl_((C≤12)),cycloalkoxy_((C≤12)), aryl_((C≤12)), aralkyl_((C≤12)),heteroaryl_((C≤12)), heterocycloalkyl_((C≤12)), acyl_((C≤12)),acyloxy_((C≤12)), alkylamino_((C≤12)), dialkylamino_((C≤12)),alkylsulfonylamino_((C≤12)), or a substituted version of any of the lastfourteen groups, or—OY₁-A₁; wherein: Y₁ is alkanediyl_((C≤8)) or substitutedalkanediyl_((C≤8)); and A₁ is cycloalkyl_((C≤8)) or substitutedcycloalkyl_((C≤8)); or—Y₂—C(O)NR_(b)—A₂; wherein: Y₂ is arenediyl_((C≤8)) or substitutedarenediyl_((C≤8)); R_(b) is hydrogen, alkyl_((C≤6)), or substitutedalkyl_((C≤6)); and A₂ is aralkyl_((C≤12)) or substitutedaralkyl_((C≤12)); or-A₃R_(d); wherein: A₃ is —O— or —NR_(e)—, wherein R_(e) is hydrogen,alkyl_((C≤6)), or substituted alkyl_((C≤6)); and R_(d) is acyl_((C≤12)),or substituted acyl_((C≤12)); or a pharmaceutically acceptable saltthereof.
 30. The method according to any one of claims 27-29, whereinthe compound is further defined as:

wherein: R₂ is hydrogen or alkyl_((C≤12)), cycloalkyl_((C≤12)),alkenyl_((C≤12)), alkynyl_((C≤12)), aryl_((C≤12)), aralkyl_((C≤12)),heteroaryl_((C≤12)), heteroaralkyl_((C≤12)), acyl_((C≤12)), or asubstituted version of any of these groups, or-alkanediyl_((C≤8))-cycloalkyl_((C≤12)) or a substituted version of thisgroup; R₄ is hydrogen, amino, alkyl_((C2-18)), substitutedalkyl_((C≤18)), cycloalkyl_((C≤18)), substituted cycloalkyl_((C≤18)),aryl_((C≤18)), substituted aryl_((C≤18)), aralkyl_((C≤18)), substitutedaralkyl_((C≤18)), heteroaryl_((C≤18)), substituted heteroaryl_((C≤18)),heteroaralkyl_((C≤18)), substituted heteroaralkyl_((C≤18)),heterocycloalkyl_((C≤18)), substituted heterocycloalkyl_((C≤18)),alkylamino_((C≤18)), substituted alkylamino_((C≤18)),dialkylamino_((C≤18)), substituted dialkylamino_((C≤18)),alkylthio_((C≤18)), substituted alkylthio_((C≤18)), amido_((C≤18)),substituted amido_((C≤18)), or—X₁—(CH₂)_(m)—R_(4′); wherein: X₁ is NR_(b), O, or S; wherein: R_(b) ishydrogen, alkyl_((C≤6)), or substituted alkyl_((C≤6)); m is 0, 1, 2, 3,or 4; and R_(4′) is alkyl_((C≤12)), cycloalkyl_((C≤18)), aryl_((C≤18)),aralkyl_((C≤18)), heteroaryl_((C≤18)), heteroaralkyl_((C≤18)),heterocycloalkyl_((C≤18)), or a substituted version of any of thesegroups, provided that when X₁ is O, then R_(4′) is not methyl; or

wherein: n is 0, 1, 2, 3, or 4; and R_(4″) is —H, —OH, —F, —Cl, —Br, —I,—NH₂, —NO₂, —CN, —SH, —S(O)₂OH, or —S(O)₂NH₂, or alkyl_((C≤8)),cycloalkyl_((C≤8)), aryl_((C≤8)), heteroaryl_((C≤8)),heterocycloalkyl_((C≤8)), acyl_((C≤8)), amido_((C≤8)), alkoxy_((C≤8)),acyloxy_((C≤8)), alkylamino_((C≤8)), dialkylamino_((C≤8)),—C(O)-alkoxy_((C≤8)), —C(O)-alkylamino_((C≤8)),—C(O)-dialkyl-amino_((C≤8)), alkylsulfonyl_((C≤8)),arylsulfonyl_((C≤8)), alkoxysulfonyl_((C≤8)), or a substituted versionof any of these groups; or—X₂—(CH₂)_(p)—R_(4′″); wherein: X₂ is arenediyl_((C≤12)), substitutedarenediyl_((C≤12)), heterocycloalkanediyl_((C≤12)), substitutedheterocycloalkanediyl_((C≤12)), heteroarenediyl_((C≤12)), or substitutedheteroarenediyl_((C≤12)); p is 0, 1, 2, 3, or 4; and R_(4′″) isalkyl_((C≤8)), cycloalkyl_((C≤8)), aryl_((C≤8)), heteroaryl_((C≤8)),heterocycloalkyl_((C≤8)), acyl_((C≤8)), amido_((C≤8)), alkoxy_((C≤8)),acyloxy_((C≤8)), —C(O)-alkoxy_((C≤8)), —C(O)-alkylamino_((C≤8)),—C(O)-dialkyl-amino_((C≤8)), alkylsulfonyl_((C≤8)),arylsulfonyl_((C≤8)), alkoxysulfonyl_((C≤8)), or a substituted versionof any of these groups; and R₅ is amino, hydroxy, —OS(O)₂C₆H₄CH₃,alkyl_((C≤12)), alkoxy_((C≤12)), cycloalkyl_((C≤12)),cycloalkoxy_((C≤12)), aryl_((C≤12)), aralkyl_((C≤12)),heteroaryl_((C≤12)), heterocycloalkyl_((C≤12)), acyl_((C≤12)),acyloxy_((C≤12)), alkylamino_((C≤12)), dialkylamino_((C≤12)),alkylsulfonylamino_((C≤12)), or a substituted version of any of the lastfourteen groups, or—OY₁-A₁; wherein: Y₁ is alkanediyl_((C≤8)) or substitutedalkanediyl_((C≤8)); and A₁ is cycloalkyl_((C≤8)) or substitutedcycloalkyl_((C≤8)); or—Y₂—C(O)NR_(b)-A₂; wherein: Y₂ is arenediyl_((C≤8)) or substitutedarenediyl_((C≤8)); R_(b) is hydrogen, alkyl_((C≤6)), or substitutedalkyl_((C≤6)); and A₂ is aralkyl_((C≤12)) or substitutedaralkyl_((C≤12)); or-A₃R_(d); wherein: A₃ is —O— or —NR_(e)—, wherein R_(e) is hydrogen,alkyl_((C≤6)), or substituted alkyl_((C≤6)); and R_(d) is acyl_((C≤12)),or substituted acyl_((C≤12)); or a pharmaceutically acceptable saltthereof.
 31. The method according to any one of claims 27-30, whereinthe compound is further defined as:

wherein: R₂ is hydrogen, alkyl_((C≤12)), or substituted alkyl_((C≤12));R₄ is heteroaryl_((C≤18)) or substituted heteroaryl_((C≤18)); and R₅ isaryl_((C≤12)) or substituted aryl_((C≤12)); or a pharmaceuticallyacceptable salt thereof.
 32. The method according to any one of claims27-30, wherein the compound is further defined as:

wherein: R₂ is alkyl_((C≤12)) or substituted alkyl_((C≤12)); HetAr isheteroaryl_((C≤18)) or substituted heteroaryl_((C≤18)); and Ar isaryl_((C≤12)) or substituted aryl_((C≤12)); or a pharmaceuticallyacceptable salt thereof.
 33. The method according to any one of claims27-32, wherein the compound is further defined as:

wherein: R₄ is heteroaryl_((C≤18)) or substituted heteroaryl_((C≤18));and R₅ is aryl_((C≤12)) or substituted aryl_((C≤12)); or apharmaceutically acceptable salt thereof.
 34. The method according toany one of claims 22-28, wherein the bond between carbon atom 1 andcarbon atom 2 is a double bond.
 35. The method of either claim 27 orclaim 34, wherein a is
 1. 36. The method according to any one of claims22-29, 34, and 35, wherein R₁ is cyano.
 37. The method according to anyone of claims 22-29 and 34-36, wherein R₂ is alkyl_((C≤12)),alkenyl_((C≤12)), or a substituted version of either group.
 38. Themethod of claim 37, wherein R₂ is alkyl_((C≤12)) or substitutedalkyl_((C≤12)).
 39. The method according to any one of claims 22-27 and34-38, wherein R_(2′) is hydrogen.
 40. The method according to any oneof claims 22-28 and 34-39, wherein R₃ is alkyl_((C≤12)), aryl_((C≤12)),or a substituted version thereof.
 41. The method of claim 40, wherein R₃is alkyl_((C≤12)) or substituted alkyl_((C≤12)).
 42. The methodaccording to any one of claims 27-41, wherein R₄ is aryl_((C≤18)),heteroaryl_((C≤18)), or a substituted version thereof.
 43. The method ofclaim 42, wherein R₄ is heteroaryl_((C≤18)) or substitutedheteroaryl_((C≤18)).
 44. The method of claim 43, wherein R₄ is aheteroaryl_((C≤12)) or a substituted heteroaryl_((C≤12)) group whereinat least one of the heteroatoms in the aromatic ring is a nitrogen atom.45. The method of claim 42, wherein R₄ is aryl_((C≤12)) or substitutedaryl_((C≤12)).
 46. The method according to any one of claims 27-45,wherein R₅ is aryl_((C≤12)), heteroaryl_((C≤12)), or a substitutedversion thereof.
 47. The method of claim 46, wherein R₅ is aryl_((C≤12))or substituted aryl_((C≤12)).
 48. The method of claim 47, wherein R₅further comprises one or more fluorine atoms.
 49. The method accordingto any one of claims 27-48, wherein the compound is further defined as:

or a pharmaceutically acceptable salt thereof.
 50. The method accordingto any one of claims 1-26, wherein the inverse agonist is a compound ofthe formula:

wherein: wherein the bond between carbon atoms 1 and 2 is an epoxidizeddouble bond or a double bond; n is 0, 1, or 2; R₁ is cyano, fluoro,—CF₃, or —C(O)R_(a), wherein: R_(a) is hydroxy or amino; oralkoxy_((C≤6)), alkylamino_((C≤6)), dialkylamino_((C≤6)), or asubstituted version of any of these groups; R₂ and R_(2′) are eachindependently hydrogen; or alkyl_((C≤12)), cycloalkyl_((C≤12)),alkenyl_((C≤12)), alkynyl_((C≤12)), aryl_((C≤18)), aralkyl_((C≤18)),heteroaryl_((C≤18)), heteroaralkyl_((C≤18)), or a substituted version ofany of these groups; or R₂ and R_(2′) are taken together and arealkanediyl_((C≤8)), alkenediyl_((C≤8)), or a substituted version ofeither of these groups; R₃ is alkyl_((C≤12)), alkenyl_((C≤12)),aryl_((C≤12)), aralkyl_((C≤12)), or a substituted version of any ofthese groups; R₄ and R₅ are each independently absent or hydrogen; oralkyl_((C≤12)), cycloalkyl_((C≤12)), heterocycloalkyl_((C≤12)),aryl_((C≤12)), aralkyl_((C≤12)), heteroaryl_((C≤12)),heteroaralkyl_((C≤12)), -arenediyl_((C≤12))-alkyl_((C≤12)),-arenediyl_((C≤12))-aryl_((C≤12)),-arenediyl_((C≤12))-heteroaryl_((C≤12)),-arenediyl_((C≤12))-heterocycloalkyl_((C≤12)),-arenediyl_((C≤12))-cyclo-alkyl_((C≤12)),-heteroarenediyl_((C≤12))-alkyl_((C≤12)),-heteroarenediyl_((C≤12))-aryl_((C≤12)),-hetero-arenediyl_((C≤12))-heteroaryl_((C≤12)),-heteroarenediyl_((C≤12))-hetero-cycloalkyl_((C≤12)),-heteroarenediyl_((C≤12))-cycloalkyl_((C≤12)),-heterocycloalkanediyl_((C≤12))-aryl_((C≤12)),-heterocycloalkanediyl_((C≤12))-heteroaryl_((C≤12)), or a substitutedversion of any of these groups; or a group of the formula:

wherein l and m are each 0, 1, 2, or 3; R₆ is absent, hydrogen, oramino; or alkylamino_((C≤12)), dialkylamino_((C≤12)),cycloalkylamino_((C≤12)), dicycloalkylamino_((C≤12)),alkyl(cycloalkyl)amino_((C≤12)), arylamino_((C≤12)),diarylamino_((C≤12)), alkyl_((C≤12)), cycloalkyl_((C≤12)),-alkanediyl_((C≤12))-cycloalkyl_((C≤12)),-alkanediyl_((C≤18))-aralkoxy_((C≤18)), heterocycloalkyl_((C≤12)),aryl_((C≤18)), -arenediyl_((C≤12))-alkyl_((C≤12)), aralkyl_((C≤18)),-arenediyl_((C≤18))-heterocycloalkyl_((C≤12)), heteroaryl_((C≤18)),-heteroarenediyl_((C≤12))-alkyl_((C≤12)), heteroaralkyl_((C≤18)),acyl_((C≤12)), alkoxy_((C≤12)), or a substituted version of any of thesegroups; and X₁ and X₂ are each independently C or N, provided that X₂ isC when R₆ is amino, alkylamino_((C≤12)), dialkylamino_((C≤12)),cycloalkylamino_((C≤12)), dicycloalkylamino_((C≤12)),alkyl(cycloalkyl)amino_((C≤12)), arylamino_((C≤12)), ordiarylamino_((C≤12)); or a pharmaceutically acceptable salt thereof. 51.The method of claim 50 further defined as:

wherein: n is 0, 1, or 2; R₁ is cyano, fluoro, —CF₃, or —C(O)R_(a),wherein R_(a) is hydroxy or amino; or alkoxy_((C≤6)),alkylamino_((C≤6)), dialkylamino_((C≤6)), or a substituted version ofany of these groups; R₂ and R_(2′) are each independently hydrogen; oralkyl_((C≤12)), cycloalkyl_((C≤12)), alkenyl_((C≤12)), alkynyl_((C≤12)),aryl_((C≤18)), aralkyl_((C≤18)), heteroaryl_((C≤18)),heteroaralkyl_((C≤18)), or a substituted version of any of these groups;or R₂ and R_(2′) are taken together and are alkanediyl_((C≤8)),alkenediyl_((C≤8)), or a substituted version of either of these groups;R₃ is alkyl_((C≤12)), alkenyl_((C≤12)), aryl_((C≤12)), aralkyl_((C≤12)),or a substituted version of any of these groups; R₄ and R₅ are eachindependently absent or hydrogen; or alkyl_((C≤12)),cycloalkyl_((C≤12)), heterocycloalkyl_((C≤12)), aryl_((C≤12)),aralkyl_((C≤12)), heteroaryl_((C≤12)), heteroaralkyl_((C≤12)),-arenediyl_((C≤12))-alkyl_((C≤12)), -arenediyl_((C≤12))-aryl_((C≤12)),-arenediyl_((C≤12))-heteroaryl_((C≤12)),-arenediyl_((C≤12))-heterocycloalkyl_((C≤12)),-arenediyl_((C≤12))-cyclo-alkyl_((C≤12)),-heteroarenediyl_((C≤12))-alkyl_((C≤12)),-heteroarenediyl_((C≤12))-aryl_((C≤12)),-hetero-arenediyl_((C≤12))-heteroaryl_((C≤12)),-heteroarenediyl_((C≤12))-hetero-cycloalkyl_((C≤12)),-heteroarenediyl_((C≤12))-cycloalkyl_((C≤12)),-heterocycloalkanediyl_((C≤12))-aryl_((C≤12)),-heterocycloalkanediyl_((C≤12))-heteroaryl_((C≤12)), or a substitutedversion of any of these groups; or a group of the formula:

wherein l and m are each 0, 1, 2, or 3; R₆ is absent, hydrogen, oramino; or alkylamino_((C≤12)), dialkylamino_((C≤12)),cycloalkylamino_((C≤12)), dicycloalkylamino_((C≤12)),alkyl(cycloalkyl)amino_((C≤12)), arylamino_((C≤12)),diarylamino_((C≤12)), alkyl_((C≤12)), cycloalkyl_((C≤12)),-alkanediyl_((C≤12))-cycloalkyl_((C≤12)),-alkanediyl_((C≤18))-aralkoxy_((C≤18)), heterocycloalkyl_((C≤12)),aryl_((C≤18)), -arenediyl_((C≤12))-alkyl_((C≤12)), aralkyl_((C≤18)),-arenediyl_((C≤18))-heterocycloalkyl_((C≤12)), heteroaryl_((C≤18)),-heteroarenediyl_((C≤12))-alkyl_((C≤12)), heteroaralkyl_((C≤18)),acyl_((C≤12)), alkoxy_((C≤12)), or a substituted version of any of thesegroups; and X₁ and X₂ are each independently C or N, provided that X₂ isC when R₆ is amino, alkylamino_((C≤12)), dialkylamino_((C≤12)),cycloalkylamino_((C≤12)), dicycloalkylamino_((C≤12)),alkyl(cycloalkyl)amino_((C≤12)), arylamino_((C≤12)), ordiarylamino_((C≤12)); or a pharmaceutically acceptable salt thereof. 52.The method of either claim 50 or claim 51 further defined as:

wherein: R₁ is cyano, fluoro, —CF₃, or —C(O)R_(a), wherein R_(a) ishydroxy or amino; or alkoxy_((C≤6)), alkylamino_((C≤6)),dialkylamino_((C≤6)), or a substituted version of any of these groups;R₂ and R_(2′) are each independently hydrogen; or alkyl_((C≤12)),cycloalkyl_((C≤12)), alkenyl_((C≤12)), alkynyl_((C≤12)), aryl_((C≤18)),aralkyl_((C≤18)), heteroaryl_((C≤18)), heteroaralkyl_((C≤18)), or asubstituted version of any of these groups; or R₂ and R_(2′) are takentogether and are alkanediyl_((C≤8)), alkenediyl_((C≤8)), or asubstituted version of either of these groups; R₄ and R₅ are eachindependently absent or hydrogen; or alkyl_((C≤12)),cycloalkyl_((C≤12)), heterocycloalkyl_((C≤12)), aryl_((C≤12)),aralkyl_((C≤12)), heteroaryl_((C≤12)), heteroaralkyl_((C≤12)),-arenediyl_((C≤12))-alkyl_((C≤12)), -arenediyl_((C≤12))-aryl_((C≤12)),-arenediyl_((C≤12))-heteroaryl_((C≤12)),-arenediyl_((C≤18))-heterocycloalkyl_((C≤12)),-arenediyl_((C≤12))-cyclo-alkyl_((C≤12)),-heteroarenediyl_((C≤12))-alkyl_((C≤12)),-heteroarenediyl_((C≤12))-aryl_((C≤12)),-heteroarenediyl_((C≤12))-heteroaryl_((C≤12)),-heteroarenediyl_((C≤12))-heterocycloalkyl_((C≤12)),-heteroarenediyl_((C≤12))-cycloalkyl_((C≤12)),-heterocycloalkanediyl_((C≤12))-aryl_((C≤12)),-heterocycloalkanediyl_((C≤12))-heteroaryl_((C≤12)), or a substitutedversion of any of these groups; or a group of the formula:

wherein l and m are each 0, 1, 2, or 3; R₆ is absent, hydrogen, oramino; or alkylamino_((C≤12)), dialkylamino_((C≤12)),cycloalkylamino_((C≤12)), dicycloalkylamino_((C≤12)),alkyl(cycloalkyl)amino_((C≤12)), arylamino_((C≤12)),diarylamino_((C≤12)), alkyl_((C≤12)), cycloalkyl_((C≤12)),-alkanediyl_((C≤12))-cycloalkyl_((C≤12)),-alkanediyl_((C≤18))-aralkoxy_((C≤18)), heterocycloalkyl_((C≤12)),aryl_((C≤18)), -arenediyl_((C≤12))-alkyl_((C≤12)), aralkyl_((C≤18)),-arenediyl_((C≤18))-heterocycloalkyl_((C≤12)), heteroaryl_((C≤18)),-heteroarenediyl_((C≤12))-alkyl_((C≤12)), heteroaralkyl_((C≤18)),acyl_((C≤12)), alkoxy_((C≤12)), or a substituted version of any of thesegroups; and X₁ and X₂ are each independently C or N, provided that X₂ isC when R₆ is amino, alkylamino_((C≤12)), dialkylamino_((C≤12)),cycloalkylamino_((C≤12)), dicycloalkylamino_((C≤12)),alkyl(cycloalkyl)amino_((C≤12)), arylamino_((C≤12)), ordiarylamino_((C≤12)); or a pharmaceutically acceptable salt thereof. 53.The method of either claim 50 or claim 51, further defined as:

wherein: R₂ and R_(2′) are each independently hydrogen; oralkyl_((C≤12)), cycloalkyl_((C≤12)), alkenyl_((C≤12)), alkynyl_((C≤12)),aryl_((C≤18)), aralkyl_((C≤18)), heteroaryl_((C≤18)),heteroaralkyl_((C≤18)), or a substituted version of any of these groups;or R₂ and R_(2′) are taken together and are alkanediyl_((C≤8)),alkenediyl_((C≤8)), or a substituted version of either of these groups;R₄ and R₅ are each independently absent or hydrogen; or alkyl_((C≤12)),cycloalkyl_((C≤12)), heterocycloalkyl_((C≤12)), aryl_((C≤12)),aralkyl_((C≤12)), heteroaryl_((C≤12)), heteroaralkyl_((C≤12)),-arenediyl_((C≤12))-alkyl_((C≤12)), -arenediyl_((C≤12))-aryl_((C≤12)),-arenediyl_((C≤12))-heteroaryl_((C≤12)),-arenediyl_((C≤12))-heterocycloalkyl_((C≤12)),-arenediyl_((C≤12))-cyclo-alkyl_((C≤12)),-heteroarenediyl_((C≤12))-alkyl_((C≤12)),-heteroarenediyl_((C≤12))-aryl_((C≤12)),-hetero-arenediyl_((C≤12))-heteroaryl_((C≤12)),-heteroarenediyl_((C≤12))-hetero-cycloalkyl_((C≤12)),-heteroarenediyl_((C≤12))-cycloalkyl_((C≤12)),-heterocycloalkanediyl_((C≤12))-aryl_((C≤12)),-heterocycloalkanediyl_((C≤12))-heteroaryl_((C≤12)), or a substitutedversion of any of these groups; or a group of the formula:

wherein l and m are each 0, 1, 2, or 3; R₆ is absent, hydrogen, oramino; or alkylamino_((C≤12)), dialkylamino_((C≤12)),cycloalkylamino_((C≤12)), dicycloalkylamino_((C≤12)),alkyl(cycloalkyl)amino_((C≤12)), arylamino_((C≤12)),diarylamino_((C≤12)), alkyl_((C≤12)), cycloalkyl_((C≤12)),-alkanediyl_((C≤12))-cycloalkyl_((C≤12)),-alkanediyl_((C≤18))-aralkoxy_((C≤18)), heterocycloalkyl_((C≤12)),aryl_((C≤18)), -arenediyl_((C≤12))-alkyl_((C≤12)), aralkyl_((C≤18)),-arenediyl_((C≤18))-heterocycloalkyl_((C≤12)), heteroaryl_((C≤18)),-heteroarenediyl_((C≤12))-alkyl_((C≤12)), heteroaralkyl_((C≤18)),acyl_((C≤12)), alkoxy_((C≤12)), or a substituted version of any of thesegroups; and X₁ and X₂ are each independently C or N, provided that X₂ isC when R₆ is amino, alkylamino_((C≤12)), dialkylamino_((C≤12)),cycloalkylamino_((C≤12)), dicycloalkylamino_((C≤12)),alkyl(cycloalkyl)amino_((C≤12)), arylamino_((C≤12)), ordiarylamino_((C≤12)); or a pharmaceutically acceptable salt thereof. 54.The method of either claim 174 or claim 51, further defined as:

wherein: R₄ and R₅ are each independently absent, hydrogen; oralkyl_((C≤12)), cycloalkyl_((C≤12)), heterocycloalkyl_((C≤12)),aryl_((C≤12)), aralkyl_((C≤12)), heteroaryl_((C≤12)),heteroaralkyl_((C≤12)), -arenediyl_((C≤12))-alkyl_((C≤12)),-arenediyl_((C≤12))-aryl_((C≤12)),-arenediyl_((C≤12))-heteroaryl_((C≤12)),-arenediyl_((C≤12))-heterocycloalkyl_((C≤12)),-arenediyl_((C≤12))-cyclo-alkyl_((C≤12)),-heteroarenediyl_((C≤12))-alkyl_((C≤12)),-heteroarenediyl_((C≤12))-aryl_((C≤12)),-hetero-arenediyl_((C≤12))-heteroaryl_((C≤12)),-heteroarenediyl_((C≤12))-hetero-cycloalkyl_((C≤12)),-heteroarenediyl_((C≤12))-cycloalkyl_((C≤12)),-heterocycloalkanediyl_((C≤12))-aryl_((C≤12)),-heterocycloalkanediyl_((C≤12))-heteroaryl_((C≤12)), or a substitutedversion of any of these groups; or a group of the formula:

wherein l and m are each 0, 1, 2, or 3; and R₆ is absent, hydrogen; oralkylamino_((C≤12)), dialkylamino_((C≤12)), cycloalkylamino_((C≤12)),dicycloalkylamino_((C≤12)), alkyl(cycloalkyl)amino_((C≤12)),arylamino_((C≤12)), diarylamino_((C≤12)), alkyl_((C≤12)),cycloalkyl_((C≤12)), -alkanediyl_((C≤12))-cycloalkyl_((C≤12)),-alkanediyl_((C≤18))-aralkoxy_((C≤18)), heterocycloalkyl_((C≤12)),aryl_((C≤18)), -arenediyl_((C≤12))-alkyl_((C≤12)), aralkyl_((C≤18)),-arenediyl_((C≤18))-heterocycloalkyl_((C≤12)), heteroaryl_((C≤18)),-heteroarenediyl_((C≤12))-alkyl_((C≤12)), heteroaralkyl_((C≤18)),acyl_((C≤12)), alkoxy_((C≤12)), or a substituted version of any of thesegroups; or a pharmaceutically acceptable salt thereof.
 55. The method ofeither claim 50 or claim 51, further defined as:

wherein: R₄ and R₅ are each independently absent, hydrogen; oralkyl_((C≤12)), cycloalkyl_((C≤12)), heterocycloalkyl_((C≤12)),aryl_((C≤12)), aralkyl_((C≤12)), heteroaryl_((C≤12)),heteroaralkyl_((C≤12)), -arenediyl_((C≤12))-alkyl_((C≤12)),-arenediyl_((C≤12))-aryl_((C≤12)),-arenediyl_((C≤12))-heteroaryl_((C≤12)),-arenediyl_((C≤12))-heterocycloalkyl_((C≤12)),-arenediyl_((C≤12))-cyclo-alkyl_((C≤12)),-heteroarenediyl_((C≤12))-alkyl_((C≤12)),-heteroarenediyl_((C≤12))-aryl_((C≤12)),-hetero-arenediyl_((C≤12))-heteroaryl_((C≤12)),-heteroarenediyl_((C≤12))-hetero-cycloalkyl_((C≤12)),-heteroarenediyl_((C≤12))-cycloalkyl_((C≤12)),-heterocycloalkanediyl_((C≤12))-aryl_((C≤12)),-heterocycloalkanediyl_((C≤12))-heteroaryl_((C≤12)), or a substitutedversion of any of these groups; or a group of the formula:

wherein l and m are each 0, 1, 2, or 3; and R₆ is absent, hydrogen; oralkylamino_((C≤12)), dialkylamino_((C≤12)), cycloalkylamino_((C≤12)),dicycloalkylamino_((C≤12)), alkyl(cycloalkyl)amino_((C≤12)),arylamino_((C≤12)), diarylamino_((C≤12)), alkyl_((C≤12)),cycloalkyl_((C≤12)), -alkanediyl_((C≤12))-cycloalkyl_((C≤12)),-alkanediyl_((C≤18))-aralkoxy_((C≤18)), heterocycloalkyl_((C≤12)),aryl_((C≤18)), -arenediyl_((C≤12))-alkyl_((C≤12)), aralkyl_((C≤18)),-arenediyl_((C≤18))-heterocycloalkyl_((C≤12)), heteroaryl_((C≤18)),-heteroarenediyl_((C≤12))-alkyl_((C≤12)), heteroaralkyl_((C≤18)),acyl_((C≤12)), alkoxy_((C≤12)), or a substituted version of any of thesegroups; or a pharmaceutically acceptable salt thereof.
 56. The methodaccording to any one of claim 22, 50, or 51, wherein R₃ isalkyl_((C≤12)) or substituted alkyl_((C≤12)).
 57. The method accordingto any one of claims 22, 50, 51, and 56, wherein R₁ is cyano.
 58. Themethod according to any one of claims 22, 50-53 and 56-57, whereinR_(2′) is hydrogen.
 59. The method according to any one of claims 22,50-53 and 56-58, wherein R₂ is hydrogen.
 60. The method according to anyone of claims 22, 50-53 and 56-58, wherein R₂ is alkyl_((C≤12)) orsubstituted alkyl_((C≤12)).
 61. The method according to any one ofclaims 50-60, wherein R₄ is absent.
 62. The method according to any oneof claims 50-60, wherein R₄ is aryl_((C≤18)), heteroaryl_((C≤18)), or asubstituted version thereof.
 63. The method of claim 62, wherein R₄ isaryl_((C≤18)) or substituted aryl_((C≤18)).
 64. The compound of claim62, wherein R₄ is heteroaryl_((C≤18)) or substitutedheteroaryl_((C≤18)).
 65. The method according to any one of claims50-64, wherein R₅ is absent.
 66. The method according to any one ofclaims 50-64, wherein R₅ is hydrogen.
 67. The method according to anyone of claims 50-64, wherein R₅ is aryl_((C≤18)), heteroaryl_((C≤18)),or a substituted version thereof.
 68. The method of claim 67, wherein R₅is aryl_((C≤18)) or substituted aryl_((C≤18)).
 69. The method of claim67, wherein R₅ is heteroaryl_((C≤18)) or substitutedheteroaryl_((C≤18)).
 70. The method according to any one of claims50-69, wherein R₆ is hydrogen.
 71. The method according to any one ofclaims 50-69, wherein R₆ is aryl_((C≤18)), heteroaryl_((C≤18)), or asubstituted version thereof.
 72. The method of claim 71, wherein R₆ isaryl_((C≤18)) or substituted aryl_((C≤18)).
 73. The method of claim 71,wherein R₆ is heteroaryl_((C≤18)) or substituted heteroaryl_((C≤18)).74. The method according to any one of claims 50-73 further defined as:

or a pharmaceutically acceptable salt of any of the above formulas. 75.The method according to any one of claims 1-74, wherein thetherapeutically effective amount is a daily dose is 0.01-100 mg ofinverse agonist per kg of body weight.
 76. The method of claim 75,wherein the daily dose is 0.05-30 mg of inverse agonist per kg of bodyweight.
 77. The method of claim 76, wherein the daily dose is 0.1-10 mgof inverse agonist per kg of body weight.
 78. The method of claim 77,wherein the daily dose is 0.1-5 mg of inverse agonist per kg of bodyweight.
 79. The method of claim 78, wherein the daily dose is 0.1-2.5 mgof inverse agonist per kg of body weight.
 80. The method according toany of claims 1-79, wherein the inverse agonist is administered as asingle dose to the patient per day.
 81. The method according to any ofclaims 1-79, wherein the inverse agonist is administered as two or moredoses to the patient per day.
 82. The method according to any one ofclaims 1-79, wherein the inverse agonist is administered orally,intraarterially or intravenously.
 83. The method according to any one ofclaims 1-82, wherein the inverse agonist is formulated as a hard or softcapsule or a tablet.
 84. A pharmaceutical composition comprising acysteine-dependent inverse agonist of nuclear receptor RORγ/RORγt in anamount sufficient to modulate the activity of nuclear receptorRORγ/RORγt when administered to a patient.
 85. The pharmaceuticalcomposition of claim 84, wherein the inverse agonist binds to cysteine476 of the nuclear receptor RORγ (see SEQ ID NO: 1) in the patient. 86.The pharmaceutical composition of claim 85, wherein the binding occursvia the formation of a covalent bond between the inverse agonist and thecysteine
 476. 87. The pharmaceutical composition of claim 85, whereinthe inverse agonist selectively binds to cysteine 476 of a nuclearreceptor RORγ in the patient.
 88. The pharmaceutical composition ofclaim 85, wherein the inverse agonist preferentially binds to cysteine476 of a nuclear receptor RORγ relative to the orthosteric bindingpocket in the ligand binding domain (LBD) of RORγ/RORγt in the patient.89. The pharmaceutical composition of claim 85, wherein the inverseagonist does not bind to any significant extent to the orthostericbinding pocket in the ligand binding domain (LBD) of RORγ/RORγt in thepatient.
 90. The pharmaceutical composition of claim 85, wherein theinverse agonist inhibits the patient's RORγ/RORγt activity withoutsignificantly affecting the patient's RORα or RORβ activity.
 91. Thepharmaceutical composition according to any one of claims 84-90, whereinthe pharmaceutical composition modulates the function of the patient'sRORγ/RORγt.
 92. The pharmaceutical composition according to any one ofclaims 84-90, wherein the pharmaceutical composition suppresses thepatient's interleukin-17A production.
 93. The pharmaceutical compositionaccording to any one of claims 84-90, wherein the pharmaceuticalcomposition selectively inhibits the patient's T helper 17 (Th17) celldifferentiation.
 94. The pharmaceutical composition according to any oneof claims 84-90, wherein the inverse agonist's RORγt-LBD-GAL4 reporterassay IC₅₀ activity is less than 1 μM.
 95. The pharmaceuticalcomposition of claim 94, wherein the inverse agonist's RORγt-LBD-GAL4reporter assay IC₅₀ activity is less than 500 nM.
 96. The pharmaceuticalcomposition of claim 95, wherein the inverse agonist's RORγt-LBD-GAL4reporter assay IC₅₀ activity is less than 100 nM.
 97. The pharmaceuticalcomposition according to any one of claims 84-90, wherein the inverseagonist's suppression of IL-17A secretion from human CD4+ T-cells assayIC₅₀ activity is less than 500 nM.
 98. The pharmaceutical composition ofclaim 97, wherein the inverse agonist's suppression of IL-17A secretionfrom human CD4+ T-cells assay IC₅₀ activity is less than 100 nM.
 99. Thepharmaceutical composition of claim 98, wherein the inverse agonist'ssuppression of IL-17A secretion from human CD4+ T-cells assay IC₅₀activity is less than 50 nM.
 100. The pharmaceutical compositionaccording to any one of claims 84-99, wherein the disease or disorder isan autoimmune disease.
 101. The pharmaceutical composition of claim 100,wherein the autoimmune disease is Crohn's disease, rheumatoid arthritis,lupus, or psoriasis.
 102. The pharmaceutical composition of claim 100,wherein the autoimmune disease is rheumatoid arthritis.
 103. Thepharmaceutical composition of claim 100, wherein the autoimmune diseaseis psoriasis.
 104. The pharmaceutical composition according to any oneof claims 84-103, wherein the chemical formula of the inverse agonistcomprises a chemical group of the formula:

wherein: the bond between carbon atoms 1 and 2 is an epoxidized doublebond or a double bond; the bond between carbon atoms 4 and 5 is a singlebond or a double bond; R₁ is cyano, heteroaryl_((C≤8)), substitutedheteroaryl_((C≤8)), —CF₃, or —C(O)R_(a); wherein: R_(a) is hydroxy,amino, or alkoxy_((C≤8)), alkylamino_((C≤8)), dialkylamino_((C≤8)),alkylsulfonylamino_((C≤8)), or a substituted version of any of thesegroups; R₂ is hydrogen or alkyl_((C≤12)), cycloalkyl_((C≤12)),alkenyl_((C≤12)), alkynyl_((C≤12)), aryl_((C≤12)), aralkyl_((C≤12)),heteroaryl_((C≤12)), heteroaralkyl_((C≤12)), acyl_((C≤12)), or asubstituted version of any of these groups, or-alkanediyl_((C≤8))-cycloalkyl_((C≤12)) or a substituted version of thisgroup; R_(2′) is absent, hydrogen, or alkyl_((C≤12)),cycloalkyl_((C≤12)), alkenyl_((C≤12)), alkynyl_((C≤12)), aryl_((C≤12)),aralkyl_((C≤12)), heteroaryl_((C≤12)), heteroaralkyl_((C≤12)),acyl_((C≤12)), or a substituted version of these groups; provided thatwhen the bond between carbon atoms 4 and 5 is a double bond then R_(2′)is absent; and R₃ is alkyl_((C≤12)), alkenyl_((C≤12)), aryl_((C≤12)),aralkyl_((C≤12)), or a substituted version of any of these groups. 105.The pharmaceutical composition of claim 104, wherein the formula isfurther defined as:

wherein: R₁ is cyano, heteroaryl_((C≤8)), substitutedheteroaryl_((C≤8)), —CF₃, or —C(O)R_(a); wherein: R_(a) is hydroxy,amino, or alkoxy_((C≤8)), alkylamino_((C≤8)), dialkylamino_((C≤8)),alkylsulfonylamino_((C≤8)), or a substituted version of any of thesegroups; R₂ is hydrogen or alkyl_((C≤12)), cycloalkyl_((C≤12)),alkenyl_((C≤12)), alkynyl_((C≤12)), aryl_((C≤12)), aralkyl_((C≤12)),heteroaryl_((C≤12)), heteroaralkyl_((C≤12)), acyl_((C≤12)), or asubstituted version of any of these groups, or-alkanediyl_((C≤8))-cycloalkyl_((C≤12)) or a substituted version of thisgroup; R_(2′) is absent, hydrogen, or alkyl_((C≤12)),cycloalkyl_((C≤12)), alkenyl_((C≤12)), alkynyl_((C≤12)), aryl_((C≤12)),aralkyl_((C≤12)), heteroaryl_((C≤12)), heteroaralkyl_((C≤12)),acyl_((C≤12)), or a substituted version of these groups; provided thatwhen the bond between carbon atoms 4 and 5 is a double bond then R_(2′)is absent; and R₃ is alkyl_((C≤12)), alkenyl_((C≤12)), aryl_((C≤12)),aralkyl_((C≤12)), or a substituted version of any of these groups. 106.The pharmaceutical composition of either claim 104 or claim 105, whereinthe formula is further defined as:

wherein: R₂ is hydrogen or alkyl_((C≤12)), cycloalkyl_((C≤12)),alkenyl_((C≤12)), alkynyl_((C≤12)), aryl_((C≤12)), aralkyl_((C≤12)),heteroaryl_((C≤12)), heteroaralkyl_((C≤12)), acyl_((C≤12)), or asubstituted version of any of these groups, or-alkanediyl_((C≤8))-cycloalkyl_((C≤12)) or a substituted version of thisgroup; R_(2′) is absent, hydrogen, or alkyl_((C≤12)),cycloalkyl_((C≤12)), alkenyl_((C≤12)), alkynyl_((C≤12)), aryl_((C≤12)),aralkyl_((C≤12)), heteroaryl_((C≤12)), heteroaralkyl_((C≤12)),acyl_((C≤12)), or a substituted version of these groups; provided thatwhen the bond between carbon atoms 4 and 5 is a double bond then R_(2′)is absent; and R₃ is alkyl_((C≤12)), alkenyl_((C≤12)), aryl_((C≤12)),aralkyl_((C≤12)), or a substituted version of any of these groups. 107.The pharmaceutical composition according to any one of claims 104-106,wherein the formula is further defined as:

wherein: R₂ is hydrogen or alkyl_((C≤12)), cycloalkyl_((C≤12)),alkenyl_((C≤12)), alkynyl_((C≤12)), aryl_((C≤12)), aralkyl_((C≤12)),heteroaryl_((C≤12)), heteroaralkyl_((C≤12)), acyl_((C≤12)), or asubstituted version of any of these groups, or-alkanediyl_((C≤8))-cycloalkyl_((C≤12)) or a substituted version of thisgroup.
 108. The pharmaceutical composition according to any one of claim104-107, wherein the formula is further defined as:


109. The pharmaceutical composition according to any one of claims84-104, wherein the inverse agonist is a compound of the formula:

wherein: the bond between carbon atoms 1 and 2 is an epoxidized doublebond or a double bond; the bond between carbon atoms 4 and 5 is a singlebond or a double bond; a is 0, 1, or 2; R₁ is cyano, heteroaryl_((C≤8)),substituted heteroaryl_((C≤8)), —CF₃, or —C(O)R_(a); wherein: R_(a) ishydroxy, amino, or alkoxy_((C≤8)), alkylamino_((C≤8)),dialkylamino_((C≤8)), alkylsulfonylamino_((C≤8)), or a substitutedversion of any of these groups; R₂ is hydrogen or alkyl_((C≤12)),cycloalkyl_((C≤12)), alkenyl_((C≤12)), alkynyl_((C≤12)), aryl_((C≤12)),aralkyl_((C≤12)), heteroaryl_((C≤12)), heteroaralkyl_((C≤12)),acyl_((C≤12)), or a substituted version of any of these groups, or-alkanediyl_((C≤8))-cycloalkyl_((C≤12)) or a substituted version of thisgroup; R_(2′) is absent, hydrogen, or alkyl_((C≤12)),cycloalkyl_((C≤12)), alkenyl_((C≤12)), alkynyl_((C≤12)), aryl_((C≤12)),aralkyl_((C≤12)), heteroaryl_((C≤12)), heteroaralkyl_((C≤12)),acyl_((C≤12)), or a substituted version of these groups; provided thatwhen the bond between carbon atoms 4 and 5 is a double bond then R_(2′)is absent; R₃ is alkyl_((C≤12)), alkenyl_((C≤12)), aryl_((C≤12)),aralkyl_((C≤12)), or a substituted version of any of these groups; R₄ ishydrogen, amino, alkyl_((C≤18)), substituted alkyl_((C≤18)),cycloalkyl_((C≤18)), substituted cycloalkyl_((C≤18)), aryl_((C≤18)),substituted aryl_((C≤18)), aralkyl_((C≤18)), substitutedaralkyl_((C≤18)), heteroaryl_((C≤18)), substituted heteroaryl_((C≤18)),heteroaralkyl_((C≤18)), substituted heteroaralkyl_((C≤18)),heterocycloalkyl_((C≤18)), substituted heterocycloalkyl_((C≤18)),amido_((C≤18)), substituted amido_((C≤18)), or—X₁—(CH₂)_(m)—R_(4′); wherein: X₁ is NR_(b), O, or S; wherein: R_(b) ishydrogen, alkyl_((C≤6)), or substituted alkyl_((C≤6)); m is 0, 1, 2, 3,or 4; and R_(4′) is alkyl_((C≤12)), cycloalkyl_((C≤12)), aryl_((C≤18)),aralkyl_((C≤18)), heteroaryl_((C≤18)), heteroaralkyl_((C≤18)),heterocycloalkyl_((C≤18)), or a substituted version of any of thesegroups; or

wherein: n is 0, 1, 2, 3, or 4; and R_(4″) is —H, —OH, —F, —Cl, —Br, —I,—NH₂, —NO₂, —CN, —SH, —S(O)₂OH, or —S(O)₂NH₂, or alkyl_((C≤8)),cycloalkyl_((C≤8)), aryl_((C≤8)), heteroaryl_((C≤8)),heterocycloalkyl_((C≤8)), acyl_((C≤8)), amido_((C≤8)), alkoxy_((C≤8)),acyloxy_((C≤8)), alkylamino_((C≤8)), dialkylamino_((C≤8)),—C(O)-alkoxy_((C≤8)), —C(O)-alkylamino_((C≤8)),—C(O)-dialkyl-amino_((C≤8)), alkylsulfonyl_((C≤8)),arylsulfonyl_((C≤8)), alkoxysulfonyl_((C≤8)), or a substituted versionof any of these groups; or—X₂—(CH₂)_(p)—R_(4′″); wherein: X₂ is arenediyl_((C≤12)), substitutedarenediyl_((C≤12)), heterocycloalkanediyl_((C≤12)), substitutedheterocycloalkanediyl_((C≤12)), heteroarenediyl_((C≤12)), or substitutedheteroarenediyl_((C≤12)); p is 0, 1, 2, 3, or 4; and R_(4′″) isalkyl_((C≤8)), cycloalkyl_((C≤8)), aryl_((C≤8)), heteroaryl_((C≤8)),heterocycloalkyl_((C≤8)), acyl_((C≤8)), amido_((C≤8)), alkoxy_((C≤8)),acyloxy_((C≤8)), —C(O)-alkoxy_((C≤8)), —C(O)-alkylamino_((C≤8)),—C(O)-dialkyl-amino_((C≤8)), alkylsulfonyl_((C≤8)),arylsulfonyl_((C≤8)), alkoxysulfonyl_((C≤8)), or a substituted versionof any of these groups; and R₅ is amino, hydroxy, —OS(O)₂C₆H₄CH₃,alkyl_((C≤12)), alkoxy_((C≤12)), cycloalkyl_((C≤12)),cycloalkoxy_((C≤12)), aryl_((C≤12)), aralkyl_((C≤12)),heteroaryl_((C≤12)), heteroaralkyl_((C≤12)), heterocycloalkyl_((C≤12)),acyl_((C≤12)), acyloxy_((C≤12)), alkylamino_((C≤12)),dialkylamino_((C≤12)), alkylsulfonylamino_((C≤12)), or a substitutedversion of any of the last fourteen groups, or—OY₁-A₁; wherein: Y₁ is alkanediyl_((C≤8)) or substitutedalkanediyl_((C≤8)); and A₁ is cycloalkyl_((C≤8)) or substitutedcycloalkyl_((C≤8)); or—Y₂—C(O)NR_(c)-A₂; wherein: Y₂ is arenediyl_((C≤8)) or substitutedarenediyl_((C≤8)); R_(e) is hydrogen, alkyl_((C≤6)), or substitutedalkyl_((C≤6)); and A₂ is aralkyl_((C≤12)) or substitutedaralkyl_((C≤12)); or—A₃R_(d); wherein: A₃ is —O— or —NR_(e)—, wherein R_(e) is hydrogen,alkyl_((C≤6)), or substituted alkyl_((C≤6)); and R_(d) is acyl_((C≤12)),or substituted acyl_((C≤12)); provided that when carbon atoms 4 and 5are joined by a double bond, then R_(2′) and the hydrogen atom at carbonatom 5 are absent; or a pharmaceutically acceptable salt thereof. 110.The pharmaceutical composition of claim 109, wherein the compound isfurther defined as:

wherein: the bond between carbon atoms 1 and 2 is an epoxidized doublebond or a double bond; R₁ is cyano, heteroaryl_((C≤8)), substitutedheteroaryl_((C≤8)), —CF₃, or —C(O)R_(a); wherein: R_(a) is hydroxy,amino, or alkoxy_((C≤8)), alkylamino_((C≤8)), dialkylamino_((C≤8)),alkylsulfonylamino_((C≤8)), or a substituted version of any of thesegroups; R₂ is hydrogen or alkyl_((C≤12)), cycloalkyl_((C≤12)),alkenyl_((C≤12)), alkynyl_((C≤12)), aryl_((C≤12)), aralkyl_((C≤12)),heteroaryl_((C≤12)), heteroaralkyl_((C≤12)), acyl_((C≤12)), or asubstituted version of any of these groups, or-alkanediyl_((C≤8))-cycloalkyl_((C≤12)) or a substituted version of thisgroup; R₃ is alkyl_((C≤12)), aryl_((C≤12)), aralkyl_((C≤12)), or asubstituted version of any of these groups; R₄ is hydrogen, amino,alkyl_((C2-18)), substituted alkyl_((C≤18)), cycloalkyl_((C≤18)),substituted cycloalkyl_((C≤18)), aryl_((C≤18)), substitutedaryl_((C≤18)), aralkyl_((C≤18)), substituted aralkyl_((C≤18)),heteroaryl_((C≤18)), substituted heteroaryl_((C≤18)),heteroaralkyl_((C≤18)), substituted heteroaralkyl_((C≤18)),heterocycloalkyl_((C≤18)), substituted heterocycloalkyl_((C≤18)),alkylamino_((C≤18)), substituted alkylamino_((C≤18)),dialkylamino_((C≤18)), substituted dialkylamino_((C≤18)),alkylthio_((C≤18)), substituted alkylthio_((C≤18)), amido_((C≤18)),substituted amido_((C≤18)), or—X₁—(CH₂)_(m)—R_(4′); wherein: X₁ is NR_(b), O, or S; wherein: R_(b) ishydrogen, alkyl_((C≤6)), or substituted alkyl_((C≤6)); m is 0, 1, 2, 3,or 4; and R_(4′) is alkyl_((C≤12)), cycloalkyl_((C≤18)), aryl_((C≤18)),aralkyl_((C≤18)), heteroaryl_((C≤18)), heteroaralkyl_((C≤18)),heterocycloalkyl_((C≤18)), or a substituted version of any of thesegroups, provided that when X₁ is O, then R_(4′) is not methyl; or

wherein: n is 0, 1, 2, 3, or 4; and R_(4″) is —H, —OH, —F, —Cl, —Br, —I,—NH₂, —NO₂, —CN, —SH, —S(O)₂OH, or —S(O)₂NH₂, or alkyl_((C≤8)),cycloalkyl_((C≤8)), aryl_((C≤8)), heteroaryl_((C≤8)),heterocycloalkyl_((C≤8)), acyl_((C≤8)), amido_((C≤8)), alkoxy_((C≤8)),acyloxy_((C≤8)), alkylamino_((C≤8)), dialkylamino_((C≤8)),—C(O)-alkoxy_((C≤8)), —C(O)-alkylamino_((C≤8)),—C(O)-dialkyl-amino_((C≤8)), alkylsulfonyl_((C≤8)),arylsulfonyl_((C≤8)), alkoxysulfonyl_((C≤8)), or a substituted versionof any of these groups; or—X₂—(CH₂)_(p)—R_(4′″); wherein: X₂ is arenediyl_((C≤12)), substitutedarenediyl_((C≤12)), heterocycloalkanediyl_((C≤12)), substitutedheterocycloalkanediyl_((C≤12)), heteroarenediyl_((C≤12)), or substitutedheteroarenediyl_((C≤12)); p is 0, 1, 2, 3, or 4; and R_(4′″) isalkyl_((C≤8)), cycloalkyl_((C≤8)), aryl_((C≤8)), heteroaryl_((C≤8)),heterocycloalkyl_((C≤8)), acyl_((C≤8)), amido_((C≤8)), alkoxy_((C≤8)),acyloxy_((C≤8)), —C(O)-alkoxy_((C≤8)), —C(O)-alkylamino_((C≤8)),—C(O)-dialkyl-amino_((C≤8)), alkylsulfonyl_((C≤8)),arylsulfonyl_((C≤8)), alkoxysulfonyl_((C≤8)), or a substituted versionof any of these groups; and R₅ is amino, hydroxy, —OS(O)₂C₆H₄CH₃,alkyl_((C≤12)), alkoxy_((C≤12)), cycloalkyl_((C≤12)),cycloalkoxy_((C≤12)), aryl_((C≤12)), aralkyl_((C≤12)),heteroaryl_((C≤12)), heterocycloalkyl_((C≤12)), acyl_((C≤12)),acyloxy_((C≤12)), alkylamino_((C≤12)), dialkylamino_((C≤12)),alkylsulfonylamino_((C≤12)), or a substituted version of any of the lastfourteen groups, or—OY₁-A₁; wherein: Y₁ is alkanediyl_((C≤8)) or substitutedalkanediyl_((C≤8)); and A₁ is cycloalkyl_((C≤8)) or substitutedcycloalkyl_((C≤8)); or—Y₂—C(O)NR_(b)-A₂; wherein: Y₂ is arenediyl_((C≤8)) or substitutedarenediyl_((C≤8)); R_(b) is hydrogen, alkyl_((C≤6)), or substitutedalkyl_((C≤6)); and A₂ is aralkyl_((C≤12)) or substitutedaralkyl_((C≤12)); or-A₃R_(d); wherein: A₃ is —O— or —NR_(e)—, wherein R_(e) is hydrogen,alkyl_((C≤6)), or substituted alkyl_((C≤6)); and R_(d) is acyl_((C≤12)),or substituted acyl_((C≤12)); or a pharmaceutically acceptable saltthereof.
 111. The pharmaceutical composition of either claim 109 orclaim 110, wherein the compound is further defined as:

wherein: R₁ is cyano, heteroaryl_((C≤8)), substitutedheteroaryl_((C≤8)), —CF₃, or —C(O)R_(a); wherein: R_(a) is hydroxy,amino, or alkoxy_((C≤8)), alkylamino_((C≤8)), dialkylamino_((C≤8)),alkylsulfonylamino_((C≤8)), or a substituted version of any of thesegroups; R₂ is hydrogen or alkyl_((C≤12)), cycloalkyl_((C≤12)),alkenyl_((C≤12)), alkynyl_((C≤12)), aryl_((C≤12)), aralkyl_((C≤12)),heteroaryl_((C≤12)), heteroaralkyl_((C≤12)), acyl_((C≤12)), or asubstituted version of any of these groups, or-alkanediyl_((C≤8))-cycloalkyl_((C≤12)) or a substituted version of thisgroup; R₄ is hydrogen, amino, alkyl_((C2-18)), substitutedalkyl_((C≤18)), cycloalkyl_((C≤18)), substituted cycloalkyl_((C≤18)),aryl_((C≤18)), substituted aryl_((C≤18)), aralkyl_((C≤18)), substitutedaralkyl_((C≤18)), heteroaryl_((C≤18)), substituted heteroaryl_((C≤18)),heteroaralkyl_((C≤18)), substituted heteroaralkyl_((C≤18)),heterocycloalkyl_((C≤18)), substituted heterocycloalkyl_((C≤18)),alkylamino_((C≤18)), substituted alkylamino_((C≤18)),dialkylamino_((C≤18)), substituted dialkylamino_((C≤18)),alkylthio_((C≤18)), substituted alkylthio_((C≤18)), amido_((C≤18)),substituted amido_((C≤18)), or—X₁—(CH₂)_(m)—R_(4′); wherein: X₁ is NR_(b), O, or S; wherein: R_(b) ishydrogen, alkyl_((C≤6)), or substituted alkyl_((C≤6)); m is 0, 1, 2, 3,or 4; and R_(4′) is alkyl_((C≤12)), cycloalkyl_((C≤18)), aryl_((C≤18)),aralkyl_((C≤18)), heteroaryl_((C≤18)), heteroaralkyl_((C≤18)),heterocycloalkyl_((C≤18)), or a substituted version of any of thesegroups, provided that when X₁ is O, then R_(4′) is not methyl; or

wherein: n is 0, 1, 2, 3, or 4; and R_(4″) is —H, —OH, —F, —Cl, —Br, —I,—NH₂, —NO₂, —CN, —SH, —S(O)₂OH, or —S(O)₂NH₂, or alkyl_((C≤8)),cycloalkyl_((C≤8)), aryl_((C≤8)), heteroaryl_((C≤8)),heterocycloalkyl_((C≤8)), acyl_((C≤8)), amido_((C≤8)), alkoxy_((C≤8)),acyloxy_((C≤8)), alkylamino_((C≤8)), dialkylamino_((C≤8)),—C(O)-alkoxy_((C≤8)), —C(O)-alkylamino_((C≤8)),—C(O)-dialkyl-amino_((C≤8)), alkylsulfonyl_((C≤8)),arylsulfonyl_((C≤8)), alkoxysulfonyl_((C≤8)), or a substituted versionof any of these groups; or—X₂—(CH₂)_(p)—R_(4′″); wherein: X₂ is arenediyl_((C≤12)), substitutedarenediyl_((C≤12)), heterocycloalkanediyl_((C≤12)), substitutedheterocycloalkanediyl_((C≤12)), heteroarenediyl_((C≤12)), or substitutedheteroarenediyl_((C≤12)); p is 0, 1, 2, 3, or 4; and R_(4′″) isalkyl_((C≤8)), cycloalkyl_((C≤8)), aryl_((C≤8)), heteroaryl_((C≤8)),heterocycloalkyl_((C≤8)), acyl_((C≤8)), amido_((C≤8)), alkoxy_((C≤8)),acyloxy_((C≤8)), —C(O)-alkoxy_((C≤8)), —C(O)-alkylamino_((C≤8)),—C(O)-dialkyl-amino_((C≤8)), alkylsulfonyl_((C≤8)),arylsulfonyl_((C≤8)), alkoxysulfonyl_((C≤8)), or a substituted versionof any of these groups; and R₅ is amino, hydroxy, —OS(O)₂C₆H₄CH₃,alkyl_((C≤12)), alkoxy_((C≤12)), cycloalkyl_((C≤12)),cycloalkoxy_((C≤12)), aryl_((C≤12)), aralkyl_((C≤12)),heteroaryl_((C≤12)), heterocycloalkyl_((C≤12)), acyl_((C≤12)),acyloxy_((C≤12)), alkylamino_((C≤12)), dialkylamino_((C≤12)),alkylsulfonylamino_((C≤12)), or a substituted version of any of the lastfourteen groups, or—OY₁-A₁; wherein: Y₁ is alkanediyl_((C≤8)) or substitutedalkanediyl_((C≤8)); and A₁ is cycloalkyl_((C≤8)) or substitutedcycloalkyl_((C≤8)); or—Y₂—C(O)NR_(b)-A₂; wherein: Y₂ is arenediyl_((C≤8)) or substitutedarenediyl_((C≤8)); R_(b) is hydrogen, alkyl_((C≤6)), or substitutedalkyl_((C≤6)); and A₂ is aralkyl_((C≤12)) or substitutedaralkyl_((C≤12)); or-A₃R_(d); wherein: A₃ is —O— or —NR_(e)—, wherein R_(e) is hydrogen,alkyl_((C≤6)), or substituted alkyl_((C≤6)); and R_(d) is acyl_((C≤12)),or substituted acyl_((C≤12)); or a pharmaceutically acceptable saltthereof.
 112. The pharmaceutical composition according to any one ofclaims 109-111, wherein the compound is further defined as:

wherein: R₂ is hydrogen or alkyl_((C≤12)), cycloalkyl_((C≤12)),alkenyl_((C≤12)), alkynyl_((C≤12)), aryl_((C≤12)), aralkyl_((C≤12)),heteroaryl_((C≤12)), heteroaralkyl_((C≤12)), acyl_((C≤12)), or asubstituted version of any of these groups, or-alkanediyl_((C≤8))-cycloalkyl_((C≤12)) or a substituted version of thisgroup; R₄ is hydrogen, amino, alkyl_((C2-18)), substitutedalkyl_((C≤18)), cycloalkyl_((C≤18)), substituted cycloalkyl_((C≤18)),aryl_((C≤18)), substituted aryl_((C≤18)), aralkyl_((C≤18)), substitutedaralkyl_((C≤18)), heteroaryl_((C≤18)), substituted heteroaryl_((C≤18)),heteroaralkyl_((C≤18)), substituted heteroaralkyl_((C≤18)),heterocycloalkyl_((C≤8)), substituted heterocycloalkyl_((C≤18)),alkylamino_((C≤18)), substituted alkylamino_((C≤18)),dialkylamino_((C≤18)), substituted dialkylamino_((C≤18)),alkylthio_((C≤18)), substituted alkylthio_((C≤18)), amido_((C≤18)),substituted amido_((C≤18)), or—X₁—(CH₂)_(m)—R_(4′); wherein: X₁ is NR_(b), O, or S; wherein: R_(b) ishydrogen, alkyl_((C≤6)), or substituted alkyl_((C≤6)); m is 0, 1, 2, 3,or 4; and R_(4′) is alkyl_((C≤12)), cycloalkyl_((C≤18)), aryl_((C≤18)),aralkyl_((C≤18)), heteroaryl_((C≤18)), heteroaralkyl_((C≤18)),heterocycloalkyl_((C≤18)), or a substituted version of any of thesegroups, provided that when X₁ is O, then R_(4′) is not methyl; or

wherein: n is 0, 1, 2, 3, or 4; and R_(4″) is —H, —OH, —F, —Cl, —Br, —I,—NH₂, —NO₂, —CN, —SH, —S(O)₂OH, or —S(O)₂NH₂, or alkyl_((C≤8)),cycloalkyl_((C≤8)), aryl_((C≤8)), heteroaryl_((C≤8)),heterocycloalkyl_((C≤8)), acyl_((C≤8)), amido_((C≤8)), alkoxy_((C≤8)),acyloxy_((C≤8)), alkylamino_((C≤8)), dialkylamino_((C≤8)),—C(O)-alkoxy_((C≤8)), —C(O)-alkylamino_((C≤8)),—C(O)-dialkyl-amino_((C≤8)), alkylsulfonyl_((C≤8)),arylsulfonyl_((C≤8)), alkoxysulfonyl_((C≤8)), or a substituted versionof any of these groups; or—X₂—(CH₂)_(p)—R_(4′″); wherein: X₂ is arenediyl_((C≤12)), substitutedarenediyl_((C≤12)), heterocycloalkanediyl_((C≤12)), substitutedheterocycloalkanediyl_((C≤12)), heteroarenediyl_((C≤12)), or substitutedheteroarenediyl_((C≤12)); p is 0, 1, 2, 3, or 4; and R_(4′″) isalkyl_((C≤8)), cycloalkyl_((C≤8)), aryl_((C≤8)), heteroaryl_((C≤8)),heterocycloalkyl_((C≤8)), acyl_((C≤8)), amido_((C≤8)), alkoxy_((C≤8)),acyloxy_((C≤8)), —C(O)-alkoxy_((C≤8)), —C(O)-alkylamino_((C≤8)),—C(O)-dialkyl-amino_((C≤8)), alkylsulfonyl_((C≤8)),arylsulfonyl_((C≤8)), alkoxysulfonyl_((C≤8)), or a substituted versionof any of these groups; and R₅ is amino, hydroxy, —OS(O)₂C₆H₄CH₃,alkyl_((C≤12)), alkoxy_((C≤12)), cycloalkyl_((C≤12)),cycloalkoxy_((C≤12)), aryl_((C≤12)), aralkyl_((C≤12)),heteroaryl_((C≤12)), heterocycloalkyl_((C≤12)), acyl_((C≤12)),acyloxy_((C≤12)), alkylamino_((C≤12)), dialkylamino_((C≤12)),alkylsulfonylamino_((C≤12)), or a substituted version of any of the lastfourteen groups, or—OY₁-A₁; wherein: Y₁ is alkanediyl_((C≤8)) or substitutedalkanediyl_((C≤8)); and A₁ is cycloalkyl_((C≤8)) or substitutedcycloalkyl_((C≤8)); or—Y₂—C(O)NR_(b)—A₂; wherein: Y₂ is arenediyl_((C≤8)) or substitutedarenediyl_((C≤8)); R_(b) is hydrogen, alkyl_((C≤6)), or substitutedalkyl_((C≤6)); and A₂ is aralkyl_((C≤12)) or substitutedaralkyl_((C≤12)); or-A₃R_(d); wherein: A₃ is —O— or —NR_(e)—, wherein R_(e) is hydrogen,alkyl_((C≤6)), or substituted alkyl_((C≤6)); and R_(d) is acyl_((C≤12)),or substituted acyl_((C≤12)); or a pharmaceutically acceptable saltthereof.
 113. The pharmaceutical composition according to any one ofclaims 109-112, wherein the compound is further defined as:

wherein: R₂ is hydrogen, alkyl_((C≤12)), or substituted alkyl_((C≤12));R₄ is heteroaryl_((C≤18)) or substituted heteroaryl_((C≤18)); and R₅ isaryl_((C≤12)) or substituted aryl_((C≤12)); or a pharmaceuticallyacceptable salt thereof.
 114. The pharmaceutical composition accordingto any one of claims 109-112, wherein the compound is further definedas:

wherein: R₂ is alkyl_((C≤12)) or substituted alkyl_((C≤12)); HetAr isheteroaryl_((C≤18)) or substituted heteroaryl_((C≤18)); and Ar isaryl_((C≤12)) or substituted aryl_((C≤12)); or a pharmaceuticallyacceptable salt thereof.
 115. The pharmaceutical composition accordingto any one of claims 109-114, wherein the compound is further definedas:

wherein: R₄ is heteroaryl_((C≤18)) or substituted heteroaryl_((C≤18));and R₅ is aryl_((C≤12)) or substituted aryl_((C≤12)); or apharmaceutically acceptable salt thereof.
 116. The pharmaceuticalcomposition according to any one of claims 104-110, wherein the bondbetween carbon atom 1 and carbon atom 2 is a double bond.
 117. Thepharmaceutical composition according to any one of claims 109 and 116,wherein a is
 1. 118. The pharmaceutical composition according to any oneof claims 104-111 and 116-117, wherein R₁ is cyano.
 119. Thepharmaceutical composition according to any one of claims 104-111 and116-118, wherein R₂ is alkyl_((C≤12)), alkenyl_((C≤12)), or asubstituted version of either group.
 120. The of claim 119, wherein R₂is alkyl_((C≤12)) or substituted alkyl_((C≤12)).
 121. The pharmaceuticalcomposition according to any one of claims 104-109 and 116-120, whereinR_(2′) is hydrogen.
 122. The pharmaceutical composition according to anyone of claims 104-109 and 116-121, wherein R₃ is alkyl_((C≤12)),aryl_((C≤12)), or a substituted version thereof.
 123. The of claim 122,wherein R₃ is alkyl_((C≤12)) or substituted alkyl_((C≤12)).
 124. Thepharmaceutical composition according to any one of claims 109-115 and116-123, wherein R₄ is aryl_((C≤18)), heteroaryl_((C≤18)), or asubstituted version thereof.
 125. The pharmaceutical composition ofclaim 124, wherein R₄ is aryl_((C≤18)) or substituted aryl_((C≤18)).126. The pharmaceutical composition of claim 125, wherein R₄ isheteroaryl_((C≤18)) or substituted heteroaryl_((C≤18)).
 127. Thepharmaceutical composition of claim 126, wherein R₄ is aheteroaryl_((C≤12)) or a substituted heteroaryl_((C≤12)) group whereinat least one of the heteroatoms in the aromatic ring is a nitrogen atom.128. The pharmaceutical composition of claim 124, wherein R₄ isaryl_((C≤12)) or substituted aryl_((C≤12)).
 129. The pharmaceuticalcomposition according to any one of claims 109-128, wherein R₅ isaryl_((C≤12)), heteroaryl_((C≤12)), or a substituted version thereof.130. The pharmaceutical composition of claim 129, wherein R₅ isaryl_((C≤12)) or substituted aryl_((C≤12)).
 131. The pharmaceuticalcomposition of claim 130, wherein R₅ further comprises one or morefluorine atoms.
 132. The pharmaceutical composition according to any oneof claims 109-131, wherein the compound is further defined as:

or a pharmaceutically acceptable salt thereof.
 133. The pharmaceuticalcomposition according to any one of claims 84-104, wherein the inverseagonist is a compound of the formula:

wherein: wherein the bond between carbon atoms 1 and 2 is an epoxidizeddouble bond or a double bond; n is 0, 1, or 2; R₁ is cyano, fluoro,—CF₃, or —C(O)R_(a), wherein: R_(a) is hydroxy or amino; oralkoxy_((C≤6)), alkylamino_((C≤6)), dialkylamino_((C≤6)), or asubstituted version of any of these groups; R₂ and R_(2′) are eachindependently hydrogen; or alkyl_((C≤12)), cycloalkyl_((C≤12)),alkenyl_((C≤12)), alkynyl_((C≤12)), aryl_((C≤18)), aralkyl_((C≤18)),heteroaryl_((C≤18)), heteroaralkyl_((C≤18)), or a substituted version ofany of these groups; or R₂ and R_(2′) are taken together and arealkanediyl_((C≤8)), alkenediyl_((C≤8)), or a substituted version ofeither of these groups; R₃ is alkyl_((C≤12)), alkenyl_((C≤12)),aryl_((C≤12)), aralkyl_((C≤12)), or a substituted version of any ofthese groups; R₄ and R₅ are each independently absent or hydrogen; oralkyl_((C≤12)), cycloalkyl_((C≤12)), heterocycloalkyl_((C≤12)),aryl_((C≤12)), aralkyl_((C≤12)), heteroaryl_((C≤12)),heteroaralkyl_((C≤12)), -arenediyl_((C≤12))-alkyl_((C≤12)),-arenediyl_((C≤12))-aryl_((C≤12)),-arenediyl_((C≤12))-heteroaryl_((C≤12)),-arenediyl_((C≤12))-heterocycloalkyl_((C≤12)),-arenediyl_((C≤12))-cyclo-alkyl_((C≤12)),-heteroarenediyl_((C≤12))-alkyl_((C≤12)),-heteroarenediyl_((C≤12))-aryl_((C≤12)),-hetero-arenediyl_((C≤12))-heteroaryl_((C≤12)),-heteroarenediyl_((C≤12))-hetero-cycloalkyl_((C≤12)),-heteroarenediyl_((C≤12))-cycloalkyl_((C≤12)),-heterocycloalkanediyl_((C≤12))-aryl_((C≤12)),-heterocycloalkanediyl_((C≤12))-heteroaryl_((C≤12)), or a substitutedversion of any of these groups; or a group of the formula:

wherein l and m are each 0, 1, 2, or 3; R₆ is absent, hydrogen, oramino; or alkylamino_((C≤12)), dialkylamino_((C≤12)),cycloalkylamino_((C≤12)), dicycloalkylamino_((C≤12)),alkyl(cycloalkyl)amino_((C≤12)), arylamino_((C≤12)),diarylamino_((C≤12)), alkyl_((C≤12)), cycloalkyl_((C≤12)),-alkanediyl_((C≤12))-cycloalkyl_((C≤12)),-alkanediyl_((C≤18))-aralkoxy_((C≤18)), heterocycloalkyl_((C≤12)),aryl_((C≤18)), -arenediyl_((C≤12))-alkyl_((C≤12)), aralkyl_((C≤18)),-arenediyl_((C≤18))-heterocycloalkyl_((C≤12)), heteroaryl_((C≤18)),-heteroarenediyl_((C≤12))-alkyl_((C≤12)), heteroaralkyl_((C≤18)),acyl_((C≤12)), alkoxy_((C≤12)), or a substituted version of any of thesegroups; and X₁ and X₂ are each independently C or N, provided that X₂ isC when R₆ is amino, alkylamino_((C≤12)), dialkylamino_((C≤12)),cycloalkylamino_((C≤12)), dicycloalkylamino_((C≤12)),alkyl(cycloalkyl)amino_((C≤12)), arylamino_((C≤12)), ordiarylamino_((C≤12)); or a pharmaceutically acceptable salt thereof.134. The pharmaceutical composition of claim 133 further defined as:

wherein: n is 0, 1, or 2; R₁ is cyano, fluoro, —CF₃, or —C(O)R_(a),wherein R_(a) is hydroxy or amino; or alkoxy_((C≤6)),alkylamino_((C≤6)), dialkylamino_((C≤6)), or a substituted version ofany of these groups; R₂ and R_(2′) are each independently hydrogen; oralkyl_((C≤12)), cycloalkyl_((C≤12)), alkenyl_((C≤12)), alkynyl_((C≤12)),aryl_((C≤18)), aralkyl_((C≤18)), heteroaryl_((C≤18)),heteroaralkyl_((C≤18)), or a substituted version of any of these groups;or R₂ and R_(2′) are taken together and are alkanediyl_((C≤8)),alkenediyl_((C≤8)), or a substituted version of either of these groups;R₃ is alkyl_((C≤12)), alkenyl_((C≤12)), aryl_((C≤12)), aralkyl_((C≤12)),or a substituted version of any of these groups; R₄ and R₅ are eachindependently absent or hydrogen; or alkyl_((C≤12)),cycloalkyl_((C≤12)), heterocycloalkyl_((C≤12)), aryl_((C≤12)),aralkyl_((C≤12)), heteroaryl_((C≤12)), heteroaralkyl_((C≤12)),-arenediyl_((C≤12))-alkyl_((C≤12)), -arenediyl_((C≤12))-aryl_((C≤12)),-arenediyl_((C≤12))-heteroaryl_((C≤12)),-arenediyl_((C≤12))-heterocycloalkyl_((C≤12)),-arenediyl_((C≤12))-cyclo-alkyl_((C≤12)),-heteroarenediyl_((C≤12))-alkyl_((C≤12)),-heteroarenediyl_((C≤12))-aryl_((C≤12)),-hetero-arenediyl_((C≤12))-heteroaryl_((C≤12)),-heteroarenediyl_((C≤12))-hetero-cycloalkyl_((C≤12)),-heteroarenediyl_((C≤12))-cycloalkyl_((C≤12)),-heterocycloalkanediyl_((C≤12))-aryl_((C≤12)),-heterocycloalkanediyl_((C≤12))-heteroaryl_((C≤12)), or a substitutedversion of any of these groups; or a group of the formula:

wherein l and m are each 0, 1, 2, or 3; R₆ is absent, hydrogen, oramino; or alkylamino_((C≤12)), dialkylamino_((C≤12)),cycloalkylamino_((C≤12)), dicycloalkylamino_((C≤12)),alkyl(cycloalkyl)amino_((C≤12)), arylamino_((C≤12)),diarylamino_((C≤12)), alkyl_((C≤12)), cycloalkyl_((C≤12)),-alkanediyl_((C≤12))-cycloalkyl_((C≤12)),-alkanediyl_((C≤18))-aralkoxy_((C≤18)), heterocycloalkyl_((C≤12)),aryl_((C≤18)), -arenediyl_((C≤12))-alkyl_((C≤12)), aralkyl_((C≤18)),-arenediyl_((C≤18))-heterocycloalkyl_((C≤12)), heteroaryl_((C≤18)),-heteroarenediyl_((C≤12))-alkyl_((C≤12)), heteroaralkyl_((C≤18)),acyl_((C≤12)), alkoxy_((C≤12)), or a substituted version of any of thesegroups; and X₁ and X₂ are each independently C or N, provided that X₂ isC when R₆ is amino, alkylamino_((C≤12)), dialkylamino_((C≤12)),cycloalkylamino_((C≤12)), dicycloalkylamino_((C≤12)),alkyl(cycloalkyl)amino_((C≤12)), arylamino_((C≤12)), ordiarylamino_((C≤12)); or a pharmaceutically acceptable salt thereof.135. The pharmaceutical composition of either claim 133 or claim 134further defined as:

wherein: R₁ is cyano, fluoro, —CF₃, or —C(O)R_(a), wherein R_(a) ishydroxy or amino; or alkoxy_((C≤6)), alkylamino_((C≤6)),dialkylamino_((C≤6)), or a substituted version of any of these groups;R₂ and R_(2′) are each independently hydrogen; or alkyl_((C≤12)),cycloalkyl_((C≤12)), alkenyl_((C≤12)), alkynyl_((C≤12)), aryl_((C≤18)),aralkyl_((C≤18)), heteroaryl_((C≤18)), heteroaralkyl_((C≤18)), or asubstituted version of any of these groups; or R₂ and R_(2′) are takentogether and are alkanediyl_((C≤8)), alkenediyl_((C≤8)), or asubstituted version of either of these groups; R₄ and R₅ are eachindependently absent or hydrogen; or alkyl_((C≤12)),cycloalkyl_((C≤12)), heterocycloalkyl_((C≤12)), aryl_((C≤12)),aralkyl_((C≤12)), heteroaryl_((C≤12)), heteroaralkyl_((C≤12)),-arenediyl_((C≤12))-alkyl_((C≤12)), -arenediyl_((C≤12))-aryl_((C≤12)),-arenediyl_((C≤12))-heteroaryl_((C≤12)),-arenediyl_((C≤18))-heterocycloalkyl_((C≤12)),-arenediyl_((C≤12))-cyclo-alkyl_((C≤12)),-heteroarenediyl_((C≤12))-alkyl_((C≤12)),-heteroarenediyl_((C≤12))-aryl_((C≤12)),-heteroarenediyl_((C≤12))-heteroaryl_((C≤12)),-heteroarenediyl_((C≤12))-heterocycloalkyl_((C≤12)),-heteroarenediyl_((C≤12))-cycloalkyl_((C≤12)),-heterocycloalkanediyl_((C≤12))-aryl_((C≤12)),-heterocycloalkanediyl_((C≤12))-heteroaryl_((C≤12)), or a substitutedversion of any of these groups; or a group of the formula:

wherein l and m are each 0, 1, 2, or 3; R₆ is absent, hydrogen, oramino; or alkylamino_((C≤12)), dialkylamino_((C≤12)),cycloalkylamino_((C≤12)), dicycloalkylamino_((C≤12)),alkyl(cycloalkyl)amino_((C≤12)), arylamino_((C≤12)),diarylamino_((C≤12)), alkyl_((C≤12)), cycloalkyl(2),-alkanediyl_((C≤12))-cycloalkyl_((C≤12)),-alkanediyl_((C≤18))-aralkoxy_((C≤18)), heterocycloalkyl_((C≤12)),aryl_((C≤18)), -arenediyl_((C≤12))-alkyl_((C≤12)), aralkyl_((C≤18)),-arenediyl_((C≤18))-heterocycloalkyl_((C≤12)), heteroaryl_((C≤18)),-heteroarenediyl_((C≤12))-alkyl_((C≤12)), heteroaralkyl_((C≤18)),acyl_((C≤12)), alkoxy_((C≤12)), or a substituted version of any of thesegroups; and X₁ and X₂ are each independently C or N, provided that X₂ isC when R₆ is amino, alkylamino_((C≤12)), dialkylamino_((C≤12)),cycloalkylamino_((C≤12)), dicycloalkylamino_((C≤12)),alkyl(cycloalkyl)amino_((C≤12)), arylamino_((C≤12)), ordiarylamino_((C≤12)); or a pharmaceutically acceptable salt thereof.136. The pharmaceutical composition according to any one of claims133-135, further defined as:

wherein: R₂ and R_(2′) are each independently hydrogen; oralkyl_((C≤12)), cycloalkyl_((C≤12)), alkenyl_((C≤12)), alkynyl_((C≤12)),aryl_((C≤18)), aralkyl_((C≤18)), heteroaryl_((C≤18)),heteroaralkyl_((C≤18)), or a substituted version of any of these groups;or R₂ and R_(2′) are taken together and are alkanediyl_((C≤8)),alkenediyl_((C≤8)), or a substituted version of either of these groups;R₄ and R₅ are each independently absent or hydrogen; or alkyl_((C≤12)),cycloalkyl_((C≤12)), heterocycloalkyl_((C≤12)), aryl_((C≤12)),aralkyl_((C≤12)), heteroaryl_((C≤12)), heteroaralkyl_((C≤12)),-arenediyl_((C≤12))-alkyl_((C≤12)), -arenediyl_((C≤12))-aryl_((C≤12)),-arenediyl_((C≤12))-heteroaryl_((C≤12)),-arenediyl_((C≤12))-heterocycloalkyl_((C≤12)),-arenediyl_((C≤12))-cyclo-alkyl_((C≤12)),-heteroarenediyl_((C≤12))-alkyl(2),-heteroarenediyl_((C≤12))-aryl_((C≤12)),-hetero-arenediyl_((C≤12))-heteroaryl_((C≤12)),-heteroarenediyl_((C≤12))-hetero-cycloalkyl_((C≤12)),-heteroarenediyl_((C≤12))-cycloalkyl_((C≤12)),-heterocycloalkanediyl_((C≤12))-aryl_((C≤12)),-heterocycloalkanediyl_((C≤12))-heteroaryl_((C≤12)), or a substitutedversion of any of these groups; or a group of the formula:

wherein l and m are each 0, 1, 2, or 3; R₆ is absent, hydrogen, oramino; or alkylamino_((C≤12)), dialkylamino_((C≤12)),cycloalkylamino_((C≤12)), dicycloalkylamino_((C≤12)),alkyl(cycloalkyl)amino_((C≤12)), arylamino_((C≤12)),diarylamino_((C≤12)), alkyl_((C≤12)), cycloalkyl_((C≤12)),-alkanediyl_((C≤12))-cycloalkyl_((C≤12)),-alkanediyl_((C≤18))-aralkoxy_((C≤18)), heterocycloalkyl_((C≤12)),aryl_((C≤18)), -arenediyl_((C≤12))-alkyl_((C≤12)), aralkyl_((C≤18)),-arenediyl_((C≤18))-heterocycloalkyl_((C≤12)), heteroaryl_((C≤18)),-heteroarenediyl_((C≤12))-alkyl_((C≤12)), heteroaralkyl_((C≤18)),acyl_((C≤12)), alkoxy_((C≤12)), or a substituted version of any of thesegroups; and X₁ and X₂ are each independently C or N, provided that X₂ isC when R₆ is amino, alkylamino_((C≤12)), dialkylamino_((C≤12)),cycloalkylamino_((C≤12)), dicycloalkylamino_((C≤12)),alkyl(cycloalkyl)amino_((C≤12)), arylamino_((C≤12)), ordiarylamino_((C≤12)); or a pharmaceutically acceptable salt thereof.137. The pharmaceutical composition according to any one of claims133-136, further defined as:

wherein: R₄ and R₅ are each independently absent, hydrogen; oralkyl_((C≤12)), cycloalkyl_((C≤12)), heterocycloalkyl_((C≤12)),aryl_((C≤12)), aralkyl_((C≤12)), heteroaryl_((C≤12)),heteroaralkyl_((C≤12)), -arenediyl_((C≤12))-alkyl_((C≤12)),-arenediyl_((C≤12))-aryl_((C≤12)),-arenediyl_((C≤12))-heteroaryl_((C≤12)),-arenediyl_((C≤12))-heterocycloalkyl_((C≤12)),-arenediyl_((C≤12))-cyclo-alkyl_((C≤12)),-heteroarenediyl_((C≤12))-alkyl_((C≤12)),-heteroarenediyl_((C≤12))-aryl_((C≤12)),-hetero-arenediyl_((C≤12))-heteroaryl_((C≤12)),-heteroarenediyl_((C≤12))-hetero-cycloalkyl_((C≤12)),-heteroarenediyl_((C≤12))-cycloalkyl(2),-heterocycloalkanediyl_((C≤12))-aryl_((C≤12)),-heterocycloalkanediyl_((C≤12))-heteroaryl_((C≤12)), or a substitutedversion of any of these groups; or a group of the formula:

wherein l and m are each 0, 1, 2, or 3; and R₆ is absent, hydrogen; oralkylamino_((C≤12)), dialkylamino_((C≤12)), cycloalkylamino_((C≤12)),dicycloalkylamino_((C≤12)), alkyl(cycloalkyl)amino_((C≤12)),arylamino_((C≤12)), diarylamino_((C≤12)), alkyl_((C≤12)),cycloalkyl_((C≤12)), -alkanediyl_((C≤12))-cycloalkyl_((C≤12)),-alkanediyl_((C≤18))-aralkoxy_((C≤18)), heterocycloalkyl_((C≤12)),aryl_((C≤18)), -arenediyl_((C≤12))-alkyl_((C≤12)), aralkyl_((C≤18)),-arenediyl_((C≤18))-heterocycloalkyl_((C≤12)), heteroaryl_((C≤18)),-heteroarenediyl_((C≤12))-alkyl_((C≤12)), heteroaralkyl_((C≤18)),acyl_((C≤12)), alkoxy_((C≤12)), or a substituted version of any of thesegroups; or a pharmaceutically acceptable salt thereof.
 138. Thepharmaceutical composition according to any one of claims 133-499,further defined as:

wherein: R₄ and R₅ are each independently absent, hydrogen; oralkyl_((C≤12)), cycloalkyl_((C≤12)), heterocycloalkyl_((C≤12)),aryl_((C≤12)), aralkyl_((C≤12)), heteroaryl_((C≤12)),heteroaralkyl_((C≤12)), -arenediyl_((C≤12))-alkyl_((C≤12)),-arenediyl_((C≤12))-aryl_((C≤12)),-arenediyl_((C≤12))-heteroaryl_((C≤12)),-arenediyl_((C≤12))-heterocycloalkyl_((C≤12)),-arenediyl_((C≤12))-cyclo-alkyl_((C≤12)),-heteroarenediyl_((C≤12))-alkyl_((C≤12)),-heteroarenediyl_((C≤12))-aryl_((C≤12)),-hetero-arenediyl_((C≤12))-heteroaryl_((C≤12)),-heteroarenediyl_((C≤12))-hetero-cycloalkyl_((C≤12)),-heteroarenediyl_((C≤12))-cycloalkyl_((C≤12)),-heterocycloalkanediyl_((C≤12))-aryl_((C≤12)),-heterocycloalkanediyl_((C≤12))-heteroaryl_((C≤12)), or a substitutedversion of any of these groups; or a group of the formula:

wherein l and m are each 0, 1, 2, or 3; and R₆ is absent, hydrogen; oralkylamino_((C≤12)), dialkylamino_((C≤12)), cycloalkylamino_((C≤12)),dicycloalkylamino_((C≤12)), alkyl(cycloalkyl)amino_((C≤12)),arylamino_((C≤12)), diarylamino_((C≤12)), alkyl_((C≤12)),cycloalkyl_((C≤12)), -alkanediyl_((C≤12))-cycloalkyl_((C≤12)),-alkanediyl_((C≤18))-aralkoxy_((C≤18)), heterocycloalkyl_((C≤12)),aryl_((C≤18)), -arenediyl_((C≤12))-alkyl_((C≤12)), aralkyl_((C≤18)),-arenediyl_((C≤18))-heterocycloalkyl_((C≤12)), heteroaryl_((C≤18)),-heteroarenediyl_((C≤12))-alkyl_((C≤12)), heteroaralkyl_((C≤18)),acyl_((C≤12)), alkoxy_((C≤12)), or a substituted version of any of thesegroups; or a pharmaceutically acceptable salt thereof.
 139. Thepharmaceutical composition according to any one of claims 104, 133, and134, wherein R₃ is alkyl_((C≤12)) or substituted alkyl_((C≤12)). 140.The pharmaceutical composition according to any one of claims 104,133-135, and 139, wherein R₁ is cyano.
 141. The pharmaceuticalcomposition according to any one of claims 104, 133-136, and 139-140,wherein R_(2′) is hydrogen.
 142. The pharmaceutical compositionaccording to any one of claims 104, 133-136, and 139-141, wherein R₂ ishydrogen.
 143. The pharmaceutical composition according to any one ofclaims 104, 133-136, and 139-141, wherein R₂ is alkyl_((C≤12)) orsubstituted alkyl_((C≤12)).
 144. The pharmaceutical compositionaccording to any one of claims 133-143, wherein R₄ is absent.
 145. Thepharmaceutical composition according to any one of claims 133-143,wherein R₄ is aryl_((C≤18)), heteroaryl_((C≤18)), or a substitutedversion thereof.
 146. The pharmaceutical composition of claim 145,wherein R₄ is aryl_((C≤18)) or substituted aryl_((C≤18)).
 147. Thepharmaceutical composition of claim 145, wherein R₄ isheteroaryl_((C≤18)) or substituted heteroaryl_((C≤18)).
 148. Thepharmaceutical composition according to any one of claims 133-147,wherein R₅ is absent.
 149. The pharmaceutical composition according toany one of claims 133-147, wherein R₅ is hydrogen.
 150. Thepharmaceutical composition according to any one of claims 133-147,wherein R₅ is aryl_((C≤18)), heteroaryl_((C≤18)), or a substitutedversion thereof.
 151. The pharmaceutical composition of claim 150,wherein R₅ is aryl_((C≤18)) or substituted aryl_((C≤18)).
 152. Thepharmaceutical composition of claim 150, wherein R₅ isheteroaryl_((C≤18)) or substituted heteroaryl_((C≤18)).
 153. Thepharmaceutical composition according to any one of claims 133-152,wherein R₆ is hydrogen.
 154. The pharmaceutical composition according toany one of claims 133-152, wherein R₆ is aryl_((C≤18)),heteroaryl_((C≤18)), or a substituted version thereof.
 155. Thepharmaceutical composition of claim 154, wherein R₆ is aryl_((C≤18)) orsubstituted aryl_((C≤18)).
 156. The pharmaceutical composition of claim154, wherein R₆ is heteroaryl_((C≤18)) or substitutedheteroaryl_((C≤18)).
 157. The pharmaceutical composition according toany one of claims 133-156, wherein the inverse agonist is a compoundfurther defined as:

or a pharmaceutically acceptable salt of any of the above formulas. 158.The pharmaceutical composition according to any one of claims 84-157,wherein the amount is a daily dose is 0.01-100 mg of inverse agonist perkg of body weight.
 159. The pharmaceutical composition of claim 158,wherein the daily dose is 0.05-30 mg of inverse agonist per kg of bodyweight.
 160. The pharmaceutical composition of claim 159, wherein thedaily dose is 0.1-10 mg of inverse agonist per kg of body weight. 161.The pharmaceutical composition of claim 160, wherein the daily dose is0.1-5 mg of inverse agonist per kg of body weight.
 162. Thepharmaceutical composition of claim 161, wherein the daily dose is0.1-2.5 mg of inverse agonist per kg of body weight.
 163. Thepharmaceutical composition according to any of claims 84-162, whereinthe pharmaceutical composition is administered as a single dose to thepatient per day.
 164. The pharmaceutical composition according to any ofclaims 84-162, wherein the pharmaceutical composition is administered astwo or more doses to the patient per day.
 165. The pharmaceuticalcomposition according to any one of claims 84-164, wherein thepharmaceutical composition is administered orally, intraarterially orintravenously.
 166. A compound of the formula:

or a pharmaceutically acceptable salt thereof.
 167. A pharmaceuticalcomposition comprising: (A) a compound according to claim 166; and (B)an excipient.
 168. The pharmaceutical composition of claim 167, whereinthe pharmaceutical composition is formulated for administration: orally,intraadiposally, intraarterially, intraarticularly, intracranially,intradermally, intralesionally, intramuscularly, intranasally,intraocularly, intrapericardially, intraperitoneally, intrapleurally,intraprostatically, intrarectally, intrathecally, intratracheally,intratumorally, intraumbilically, intravaginally, intravenously,intravesicularlly, intravitreally, liposomally, locally, mucosally,parenterally, rectally, subconjunctival, subcutaneously, sublingually,topically, transbuccally, transdermally, vaginally, in crèmes, in lipidcompositions, via a catheter, via a lavage, via continuous infusion, viainfusion, via inhalation, via injection, via local delivery, or vialocalized perfusion.
 169. The pharmaceutical composition of claim 168,wherein the pharmaceutical composition is formulated for oraladministration.
 170. The pharmaceutical composition of claim 168,wherein the pharmaceutical composition is formulated for administrationvia injection.
 171. The pharmaceutical composition of claim 170, whereinthe pharmaceutical composition is formulated for intraarterialadministration, intramuscular administration, intraperitonealadministration, or intravenous administration.
 172. The pharmaceuticalcomposition of claim 168, wherein the pharmaceutical composition isformulated for administration topically.
 173. The pharmaceuticalcomposition of claim 172, wherein the pharmaceutical composition isformulated for topical administration to the skin or to the eye. 174.The pharmaceutical composition according to any one of claims 167-173,wherein the pharmaceutical composition is formulated as a unit dose.